|
1
|
Liu S, Zhu R, Zhang Y, Jiang Z, Chen Y, Song Q, Wang F. Targeting PI3K-mTOR signaling in the anterior cingulate cortex improves emotional behavior, and locomotor activity in rats with bone cancer pain. Ann Med Surg (Lond) 2025; 87:1985-1994. [PMID: 40212145 PMCID: PMC11981390 DOI: 10.1097/ms9.0000000000003206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Accepted: 03/09/2025] [Indexed: 04/13/2025] Open
Abstract
Objective To investigate the effects of targeting the PI3K-mTOR signaling pathway in the anterior cingulate cortex (ACC) on pain responses, locomotor activity, and emotional behavior in rats with bone cancer pain. Methods Bone cancer pain was induced by implanting Walker 256 cells into the rat. Pain responses were assessed using paw withdrawal threshold and latency measurements, while locomotor activity and negative mood were evaluated through open field and conditioned place aversion tests, respectively. Results The results showed that the bone cancer pain model led to allodynia, hyperalgesia, decreased ambulation, and ACC microglial activation. Morphine treatment improved pain responses but did not affect locomotor activity or mTOR protein expression. In contrast, rapamycin treatment reduced pain, improved locomotor activity, and decreased negative mood. It also downregulated PI3K-mTOR protein expression. Furthermore, inhibiting the PI3K-mTOR pathway with a PI3K inhibitor or rapamycin not only improved pain responses and locomotor activity but also reduced depression and anxiety-like behaviors. These effects were accompanied by changes in paw withdrawal threshold, latency, static time, and PI3K-mTOR protein expression. Conclusions Targeting the PI3K-mTOR signaling pathway in the ACC effectively alleviates pain-related symptoms and emotional disturbances in rats with bone cancer pain. This approach holds promise for alleviating pain and allaying negative emotion after further study.
Collapse
Affiliation(s)
- Shuyun Liu
- Department of Anesthesiology, Shaoxing People’s Hospital, Shaoxing, China
| | - Rujia Zhu
- School of Medicine, Shaoxing University, Shaoxing, China
| | - Yuan Zhang
- Department of Anesthesiology, Shaoxing People’s Hospital, Shaoxing, China
| | - Zongming Jiang
- Department of Anesthesiology, Shaoxing People’s Hospital, Shaoxing, China
| | - Yonghao Chen
- Department of Anesthesiology, Shanghai Jiang Qiao Hospital, Shanghai, China
| | - Qiliang Song
- Department of Anesthesiology, Shaoxing People’s Hospital, Shaoxing, China
| | - Fei Wang
- Bioinformation Branch, Hangzhou Hibio Bioinformation Technology Company, HangZhou, China
| |
Collapse
|
|
2
|
Wang Y, Dong L, Han S, You Y, Zhang M, Sun B, Ni H, Ge R, Liu J, Yu J. Zingerone alleviates inflammatory pain by reducing the intrinsic excitability of anterior cingulate cortex neurons in a mice model. Front Pharmacol 2025; 16:1543594. [PMID: 40135239 PMCID: PMC11933028 DOI: 10.3389/fphar.2025.1543594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 02/12/2025] [Indexed: 03/27/2025] Open
Abstract
Background Zingiber officinale Roscoe has been shown to possess analgesic properties. Zingerone (ZO), a bioactive compound derived from Zingiber officinale Roscoe, exhibits a range of pharmacological effects, including anti-inflammatory, anti-cancer, antioxidant, antibacterial, and anti-apoptotic activities. However, the analgesic properties of zingerone remain unclear. Methods Complete Freund's adjuvant (CFA) was administered to the left hind paw of C57BL/6 mice to induce a model of inflammatory pain. The analgesic effects of zingerone were assessed using the Von Frey and Hargreaves tests. In vivo fiber photometry and whole-cell patch clamp techniques were employed to investigate the potential mechanisms. Results Both acute and long-term treatment with zingerone resulted in a significant increase in mechanical and thermal pain thresholds in mice experiencing CFA-induced inflammatory pain. Mechanical stimulation led to a pronounced increase in calcium levels within the anterior cingulate cortex (ACC) neurons of the inflammatory pain model, which was alleviated by zingerone administration. Furthermore, zingerone was found to modify synaptic transmission to ACC neurons and decrease their intrinsic excitability by prolonging the refractory period of these neurons. Conclusion Zingerone demonstrates potential for alleviating CFA-induced inflammatory pain by reducing the intrinsic excitability of ACC neurons in a mouse model.
Collapse
Affiliation(s)
- Yuanyuan Wang
- Department of Neurosurgery, the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
- Laboratory of Brain and Psychiatric Disease, Bengbu Medical University, Bengbu, Anhui, China
- School of Basic Medicine, Bengbu Medical University, Bengbu, Anhui, China
| | - Lang Dong
- Department of Neurosurgery, the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
- Laboratory of Brain and Psychiatric Disease, Bengbu Medical University, Bengbu, Anhui, China
| | - Shu Han
- Laboratory of Brain and Psychiatric Disease, Bengbu Medical University, Bengbu, Anhui, China
| | - Yuehan You
- Laboratory of Brain and Psychiatric Disease, Bengbu Medical University, Bengbu, Anhui, China
| | - Mingrui Zhang
- Laboratory of Brain and Psychiatric Disease, Bengbu Medical University, Bengbu, Anhui, China
| | - Bingjing Sun
- Laboratory of Brain and Psychiatric Disease, Bengbu Medical University, Bengbu, Anhui, China
- School of Basic Medicine, Bengbu Medical University, Bengbu, Anhui, China
| | - Hong Ni
- Laboratory of Brain and Psychiatric Disease, Bengbu Medical University, Bengbu, Anhui, China
- School of Basic Medicine, Bengbu Medical University, Bengbu, Anhui, China
| | - Rongjing Ge
- Laboratory of Brain and Psychiatric Disease, Bengbu Medical University, Bengbu, Anhui, China
- School of Basic Medicine, Bengbu Medical University, Bengbu, Anhui, China
| | - Jianhong Liu
- Laboratory of Brain and Psychiatric Disease, Bengbu Medical University, Bengbu, Anhui, China
- Department of Biochemistry and Molecular biology, School of Laboratory Medicine, Bengbu Medical University, Bengbu, Anhui, China
| | - Jiandong Yu
- Department of Neurosurgery, the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
- Laboratory of Brain and Psychiatric Disease, Bengbu Medical University, Bengbu, Anhui, China
- Anhui Engineering Research Center for Neural Regeneration Technology and Medical New Materials, Bengbu Medical University, Bengbu, Anhui, China
| |
Collapse
|
|
3
|
Shen W, Chen F, Tang Y, Zhao Y, Zhu L, Xiang L, Ning L, Zhou W, Chen Y, Wang L, Li J, Huang H, Zeng LH. mGluR5-mediated astrocytes hyperactivity in the anterior cingulate cortex contributes to neuropathic pain in male mice. Commun Biol 2025; 8:266. [PMID: 39979531 PMCID: PMC11842833 DOI: 10.1038/s42003-025-07733-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 02/13/2025] [Indexed: 02/22/2025] Open
Abstract
Astrocytes regulate synaptic transmission in healthy and pathological conditions, but their involvement in modulating synaptic transmission in chronic pain is unknown. Our study demonstrates that astrocytes in the anterior cingulate cortex (ACC) exhibit abnormal calcium signals and induce the release of glutamate in male mice. This leads to an elevation in extracellular glutamate concentration, activation of presynaptic kainate receptors, and an increase in synaptic transmission following neuropathic pain. We discovered that the abnormal calcium signals are caused by the reappearance of metabotropic glutamate receptor type 5 (mGluR5) in astrocytes in male mice. Importantly, when we specifically inhibit the Gq pathway using iβARK and reduce the expression of mGluR5 in astrocytes through shRNA, we observe a restoration of astrocytic calcium activity, normalization of synaptic transmission and extracellular concentration of glutamate, and improvement in mechanical allodynia in male mice. Furthermore, the activation of astrocytes through chemogenetics results in an overabundance of excitatory synaptic transmission, exacerbating mechanical allodynia in mice with neuropathic pain, but not in sham-operated male mice. In summary, our findings suggest that the abnormal calcium signaling in astrocytes, mediated by mGluR5, plays a crucial role in enhancing synaptic transmission in ACC and contributing to mechanical allodynia in male mice.
Collapse
Affiliation(s)
- Weida Shen
- Anji People's Hospital, Affiliated Anji Hospital, School of Medicine, Hangzhou City University, Hangzhou, China.
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, China.
| | - Fujian Chen
- Anji People's Hospital, Affiliated Anji Hospital, School of Medicine, Hangzhou City University, Hangzhou, China
| | - Yejiao Tang
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, China
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, Hangzhou, China
| | - Yulu Zhao
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, China
| | - Linjing Zhu
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, China
| | - Liyang Xiang
- School of Medicine, Nankai University, Tianjin, China
| | - Li Ning
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Wen Zhou
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, China
| | - Yiran Chen
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, China
| | - Liangxue Wang
- Anji People's Hospital, Affiliated Anji Hospital, School of Medicine, Hangzhou City University, Hangzhou, China
| | - Jing Li
- Anji People's Hospital, Affiliated Anji Hospital, School of Medicine, Hangzhou City University, Hangzhou, China
| | - Hui Huang
- Anji People's Hospital, Affiliated Anji Hospital, School of Medicine, Hangzhou City University, Hangzhou, China
| | - Ling-Hui Zeng
- Anji People's Hospital, Affiliated Anji Hospital, School of Medicine, Hangzhou City University, Hangzhou, China.
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, China.
| |
Collapse
|
|
4
|
Hu J, Ji WJ, Liu GY, Su XH, Zhu JM, Hong Y, Xiong YF, Zhao YY, Li WP, Xie W. IDO1 modulates pain sensitivity and comorbid anxiety in chronic migraine through microglial activation and synaptic pruning. J Neuroinflammation 2025; 22:42. [PMID: 39966822 PMCID: PMC11837436 DOI: 10.1186/s12974-025-03367-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 02/03/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Chronic migraine is a prevalent and potentially debilitating neurological disorder that is often comorbid with mental health conditions (such as anxiety and depression), but the underlying mechanisms linking these conditions remain poorly understood. Indoleamine 2,3-dioxygenase 1 (IDO1) has been implicated in inflammatory processes, including neuroinflammation and pain. However, its role as a link between neuroinflammation and pain sensitization in chronic migraine is not well defined. METHODS Male mice were used to establish a model of chronic migraine by recurrent intraperitoneal injections of nitroglycerin (NTG, 10 mg/kg). Using pharmacological approaches, transgenic strategies and adeno-associated virus (AAV) intervention, we investigated the role of IDO1 in pain sensitization and migraine-related mood disorders in an NTG-induced chronic migraine mouse model. We employed a combination of immunoblotting, immunohistochemistry, three-dimensional reconstruction, RNA sequencing, electrophysiology, in vivo fiber photometry, and behavioral assays to elucidate the underlying mechanisms involved. RESULTS Our findings demonstrated that pharmacological inhibition and genetic knockout of IDO1 significantly alleviated pain sensitivity in a chronic migraine model. Neuronal activity in the anterior cingulate cortex (ACC) was evaluated with in vitro c-Fos immunostaining as well as in vivo fiber photometry, and a shift in the excitation/inhibition (E/I) balance toward excitation was observed through whole-cell patch clamp recording. Notably, IDO1 expression was increased in the ACC, and AAV-mediated IDO1 knockdown in the ACC rescued pain sensitivity, electrophysiological E/I balance changes, and anxiety-like behavior in chronic migraine model mice. Furthermore, IDO1 regulated microglial activation and pruning of neuronal synapses in the ACC. IDO1's microglial pruning function appears to be mediated through the interferon (IFN) signaling pathway, and the behavioral changes induced by IDO1 knockdown in the ACC could be reversed by activating this pathway. CONCLUSIONS Our findings revealed that microglial IDO1 in the ACC drives pain sensitization and anxiety in chronic migraine, highlighting IDO1 as a potential therapeutic target for chronic migraine treatment.
Collapse
Affiliation(s)
- Jiao Hu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China
- Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Guangzhou, 510515, China
| | - Wen-Juan Ji
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China
- Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Guangzhou, 510515, China
| | - Gui-Yu Liu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China
- Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Guangzhou, 510515, China
| | - Xiao-Hong Su
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
| | - Jun-Ming Zhu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China
- Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Guangzhou, 510515, China
| | - Yu Hong
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Yi-Fan Xiong
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Yun-Yan Zhao
- Department of Critical Care Medicine, The Affiliated Traditional Chinese Medicine Hospital of Guangzhou Medical University, Guangzhou, 510130, China.
| | - Wei-Peng Li
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China.
- Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Guangzhou, 510515, China.
- Department of Neurology, Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, Guangzhou, 510317, China.
| | - Wei Xie
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China.
- Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Guangzhou, 510515, China.
| |
Collapse
|
|
5
|
Elsharkawy H, Clark JD, El-Boghdadly K. Evidence for regional anesthesia in preventing chronic postsurgical pain. Reg Anesth Pain Med 2025; 50:153-159. [PMID: 39909548 DOI: 10.1136/rapm-2024-105611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 11/05/2024] [Indexed: 02/07/2025]
Abstract
Chronic postsurgical pain (CPSP) is a common adverse outcome following surgical procedures. Despite ongoing research, the risk factors and effective strategies for mitigating CPSP remain uncertain. Regional anesthesia is a potentially beneficial yet debated intervention for mitigating the risk of CPSP. This review will delve into the mechanistic aspects of regional anesthesia and critically assess the current literature to provide a thorough understanding of its role and effectiveness. The incidence and severity of CPSP are linked to nerve damage, neuroplastic changes and immunological responses. Although numerous mechanisms contributing to CPSP have been identified, translational research is sparse, and findings are often inconsistent. Evidence suggests that regional anesthetic techniques could have a role in reducing CPSP risk across various clinical scenarios. Techniques studied include wound infiltration, peripheral nerve blocks, fascial plane blocks, thoracic paravertebral blocks and epidural anesthesia. Current data indicate that epidural anesthesia might decrease CPSP risk following thoracotomy, wound infiltration may be effective after major breast surgery and cesarean delivery, and serratus anterior plane block or pectoralis/interpectoral plane blocks might be beneficial in breast surgery. However, the existing evidence is limited and marked by several constraints especially the multifactorial causes, underscoring the need for further research in this area.
Collapse
Affiliation(s)
- Hesham Elsharkawy
- Anesthesiology Pain, MetroHealth Medical Center, Cleveland, Ohio, USA
- Professor of Anesthesiology, Case Western Reserve University, Cleveland, Ohio, USA
- Outcomes Research Consortium, Houston, Texas, USA
| | | | - Kariem El-Boghdadly
- Department of Anaesthesia and Perioperative Medicine, Guy's and St Thomas' NHS Foundation Trust, London, UK
| |
Collapse
|
|
6
|
Ambron R. Dualism, Materialism, and the relationship between the brain and the mind in experiencing pain. Neuroscience 2024; 561:139-143. [PMID: 39426707 DOI: 10.1016/j.neuroscience.2024.10.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 08/16/2024] [Accepted: 10/08/2024] [Indexed: 10/21/2024]
Abstract
Characterizing the relationship between the brain and the mind is essential, both for understanding how we experience sensations and for attempts to create machine-based artificial intelligence. Materialists argue that the brain and the mind are both physical/material in nature whereas Cartesian dualists posit that the brain is material, the mind is non-material, and that they are separate. Recent investigations into the mechanisms responsible for pain can resolve this issue. Pain from an injury requires both the induction of a long-term potentiation (LTP) in a subset of pyramidal neurons in the anterior cingulate cortex and the creation of electromagnetic waves in the surrounding area. The LTP sensitizes synaptic transmission and, by activating enzyme cascades, changes the phenotype of the pyramidal neurons. The changes sustain the generation of the waves and the pain. The waves rapidly disseminate information about the pain to distant areas of the brain and studies using Transcranial Stimulation show that EM waves can influence the induction of LTP. According to leading contemporary theories, the waves will communicate with the mind, which is where the painfulness is experienced. The material brain and immaterial mind are therefore separate and we can no longer attribute painfulness solely to the activities of the brain. This is a radical departure from the contemporary view of brain functions and supports Cartesian Dualism. Consequently, consciousness and higher mental functions cannot be duplicated by mimicking the activities of the brain.
Collapse
Affiliation(s)
- Richard Ambron
- Cell Biology, Anatomy, and Pathology, Vagelos College of Physicians and Surgeons, Columbia University, New York, USA.
| |
Collapse
|
|
7
|
Shrinidhi A, Dwyer TS, Scott JA, Watts VJ, Flaherty DP. Pyrazolo-Pyrimidinones with Improved Solubility and Selective Inhibition of Adenylyl Cyclase Type 1 Activity for Treatment of Inflammatory Pain. J Med Chem 2024; 67:18290-18316. [PMID: 39404162 DOI: 10.1021/acs.jmedchem.4c01645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Abstract
Adenylyl cyclase isoform 1 (AC1) is considered a promising target for treating inflammatory pain. Our group identified the pyrazolyl-pyrimidinone scaffold as potent and selective inhibitors of Ca2+/CaM-mediated AC1 activity; however, the molecules suffered from poor aqueous solubility. The current study presents a strategy to improve aqueous solubility of the scaffold by reduction of crystal packing energy and increasing rotational degrees of freedom within the molecule. Structure-activity and property relationship studies identified the second generation lead 7-47A (AC10142A) that demonstrated and AC1 IC50 value of 0.26 μM and aqueous solubility of 74 ± 7 μM. After in vitro ADME characterization, the scaffold advanced to in vivo pharmacokinetic evaluation, demonstrating adequate levels of exposure. Finally, 7-47A exhibited antiallodynic efficacy in a rat complete Freund's adjuvant model for inflammatory pain showing improvement over previous iterations of this scaffold. These results further validate AC1 inhibition as a viable therapeutic strategy for treating chronic and inflammatory pain.
Collapse
Affiliation(s)
- Annadka Shrinidhi
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States
| | - Tiffany S Dwyer
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States
| | - Jason A Scott
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States
| | - Val J Watts
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States
- Purdue Institute for Drug Discovery, West Lafayette, Indiana 47907, United States
- Purdue Institute for Integrative Neuroscience, 207 South Martin Jischke Dr., West Lafayette, Indiana 47907, United States
| | - Daniel P Flaherty
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States
- Purdue Institute for Drug Discovery, West Lafayette, Indiana 47907, United States
- Purdue Institute for Integrative Neuroscience, 207 South Martin Jischke Dr., West Lafayette, Indiana 47907, United States
| |
Collapse
|
|
8
|
Ambron R. Synaptic sensitization in the anterior cingulate cortex sustains the consciousness of pain via synchronized oscillating electromagnetic waves. Front Hum Neurosci 2024; 18:1462211. [PMID: 39323956 PMCID: PMC11422113 DOI: 10.3389/fnhum.2024.1462211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 08/29/2024] [Indexed: 09/27/2024] Open
Abstract
A recent report showed that experiencing pain requires not only activities in the brain, but also the generation of electric fields in a defined area of the anterior cingulate cortex (ACC). The present manuscript presents evidence that electromagnetic (EM) waves are also necessary. Action potentials (APs) encoding information about an injury stimulate thousands synapses on pyramidal neurons within the ACC resulting in the generation of synchronized oscillating (EM) waves and the activation of NMDA receptors. The latter induces a long-term potentiation (LTP) in the pyramidal dendrites that is necessary to experience both neuropathic and visceral pain. The LTP sensitizes transmission across the synapses that sustains the duration of the waves and the pain, EM waves containing information about the injury travel throughout the brain and studies using transcranial stimulation indicate that they can induce NMDA-mediated LTP in distant neuronal circuits. What is ultimately experienced as pain depends on the almost instantaneous integration of information from numerous neuronal centers, such as the amygdala, that are widely separated in the brain. These centers also generate EM waves and I propose that the EM waves from these centers interact to rapidly adjust the intensity of the pain to accommodate past and present circumstances. Where the waves are transformed into a consciousness of pain is unknown. One possibility is the mind which, according to contemporary theories, is where conscious experiences arise. The hypothesis can be tested directly by blocking the waves from the ACC. If correct, the waves would open new avenues of research into the relationship between the brain, consciousness, and the mind.
Collapse
|
|
9
|
Pagliusi M, Amorim-Marques AP, Lobo MK, Guimarães FS, Lisboa SF, Gomes FV. The rostral ventromedial medulla modulates pain and depression-related behaviors caused by social stress. Pain 2024; 165:1814-1823. [PMID: 38661577 DOI: 10.1097/j.pain.0000000000003257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 12/18/2023] [Indexed: 04/26/2024]
Abstract
ABSTRACT The rostral ventromedial medulla (RVM) is a crucial structure in the descending pain modulatory system, playing a key role as a relay for both the facilitation and inhibition of pain. The chronic social defeat stress (CSDS) model has been widely used to study stress-induced behavioral impairments associated with depression in rodents. Several studies suggest that CSDS also causes changes related to chronic pain. In this study, we aimed to investigate the involvement of the RVM in CSDS-induced behavioral impairments, including those associated with chronic pain. We used chemogenetics to activate or inhibit the RVM during stress. The results indicated that the RVM is a vital hub influencing stress outcomes. Rostral ventromedial medulla activation during CSDS ameliorates all the stress outcomes, including social avoidance, allodynia, hyperalgesia, anhedonia, and behavioral despair. In addition, RVM inhibition in animals exposed to a subthreshold social defeat stress protocol induces a susceptible phenotype, facilitating all stress outcomes. Finally, chronic RVM inhibition-without any social stress stimulus-induces chronic pain but not depressive-like behaviors. Our findings provide insights into the comorbidity between chronic pain and depression by indicating the involvement of the RVM in establishing social stress-induced behavioral responses associated with both chronic pain and depression.
Collapse
Affiliation(s)
- Marco Pagliusi
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Anna P Amorim-Marques
- Department of Biomolecular Sciences, Ribeirão Preto Pharmaceutical Sciences School, University of São Paulo, Ribeirão Preto, Brazil
| | - Mary Kay Lobo
- Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Francisco S Guimarães
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Sabrina F Lisboa
- Department of Biomolecular Sciences, Ribeirão Preto Pharmaceutical Sciences School, University of São Paulo, Ribeirão Preto, Brazil
| | - Felipe V Gomes
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| |
Collapse
|
|
10
|
Guo H, Hu WC, Xian H, Shi YX, Liu YY, Ma SB, Pan KQ, Wu SX, Xu LY, Luo C, Xie RG. CCL2 Potentiates Inflammation Pain and Related Anxiety-Like Behavior Through NMDA Signaling in Anterior Cingulate Cortex. Mol Neurobiol 2024; 61:4976-4991. [PMID: 38157119 DOI: 10.1007/s12035-023-03881-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 12/06/2023] [Indexed: 01/03/2024]
Abstract
Previous studies have shown that the C-C motif chemokine ligand 2 (CCL2) is widely expressed in the nervous system and involved in regulating the development of chronic pain and related anxiety-like behaviors, but its precise mechanism is still unclear. This paper provides an in-depth examination of the involvement of CCL2-CCR2 signaling in the anterior cingulate cortex (ACC) in intraplantar injection of complete Freund's adjuvant (CFA) leading to inflammatory pain and its concomitant anxiety-like behaviors by modulation of glutamatergic N-methyl-D-aspartate receptor (NMDAR). Our findings suggest that local bilateral injection of CCR2 antagonist in the ACC inhibits CFA-induced inflammatory pain and anxiety-like behavior. Meanwhile, the expression of CCR2 and CCL2 was significantly increased in ACC after 14 days of intraplantar injection of CFA, and CCR2 was mainly expressed in excitatory neurons. Whole-cell patch-clamp recordings showed that the CCR2 inhibitor RS504393 reduced the frequency of miniature excitatory postsynaptic currents (mEPSC) in ACC, and CCL2 was involved in the regulation of NMDAR-induced current in ACC neurons in the pathological state. In addition, local injection of the NR2B inhibitor of NMDAR subunits, Ro 25-6981, attenuated the effects of CCL2-induced hyperalgesia and anxiety-like behavior in the ACC. In summary, CCL2 acts on CCR2 in ACC excitatory neurons and participates in the regulation of CFA-induced pain and related anxiety-like behaviors through upregulation of NR2B. CCR2 in the ACC neuron may be a potential target for the treatment of chronic inflammatory pain and pain-related anxiety.
Collapse
Affiliation(s)
- Huan Guo
- Department of Basic Medical Sciences, Shantou University Medical College, No.22, Xinling Road, Shantou, 515041, China
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Wen-Chao Hu
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Hang Xian
- Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Yun-Xin Shi
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
- School of Life Science & Research Center for Resource Peptide Drugs, Shaanxi Engineering & Technological Research Center for Conversation & Utilization of Regional Biological Resources, Yanan University, Yanan, 716000, China
| | - Yuan-Ying Liu
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
- School of Life Science & Research Center for Resource Peptide Drugs, Shaanxi Engineering & Technological Research Center for Conversation & Utilization of Regional Biological Resources, Yanan University, Yanan, 716000, China
| | - Sui-Bin Ma
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, 361102, China
| | - Kun-Qing Pan
- No.19 Cadet Regiment, School of Basic Medical Sciences, Fourth Military Medical University, Xi'an, 710032, China
| | - Sheng-Xi Wu
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Li-Yan Xu
- Department of Basic Medical Sciences, Shantou University Medical College, No.22, Xinling Road, Shantou, 515041, China.
| | - Ceng Luo
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.
| | - Rou-Gang Xie
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.
| |
Collapse
|
|
11
|
Song Q, Li XH, Lu JS, Chen QY, Liu RH, Zhou SB, Zhuo M. Enhanced long-term potentiation in the anterior cingulate cortex of tree shrew. Philos Trans R Soc Lond B Biol Sci 2024; 379:20230240. [PMID: 38853555 PMCID: PMC11343311 DOI: 10.1098/rstb.2023.0240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 12/01/2023] [Accepted: 01/02/2024] [Indexed: 06/11/2024] Open
Abstract
Synaptic plasticity is a key cellular model for learning, memory and chronic pain. Most previous studies were carried out in rats and mice, and less is known about synaptic plasticity in non-human primates. In the present study, we used integrative experimental approaches to study long-term potentiation (LTP) in the anterior cingulate cortex (ACC) of adult tree shrews. We found that glutamate is the major excitatory transmitter and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid (AMPA) receptors mediate postsynaptic responses. LTP in tree shrews was greater than that in adult mice and lasted for at least 5 h. N-methyl-d-aspartic acid (NMDA) receptors, Ca2+ influx and adenylyl cyclase 1 (AC1) contributed to tree shrew LTP. Our results suggest that LTP is a major form of synaptic plasticity in the ACC of primate-like animals. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Collapse
Affiliation(s)
- Qian Song
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi’an Jiaotong University, Xi’an710049, People's Republic of China
- Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Core Facilities Sharing Platform, Xi’an Jiaotong University, Xi’an710049, People's Republic of China
| | - Xu-Hui Li
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi’an Jiaotong University, Xi’an710049, People's Republic of China
| | - Jing-Shan Lu
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi’an Jiaotong University, Xi’an710049, People's Republic of China
| | - Qi-Yu Chen
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi’an Jiaotong University, Xi’an710049, People's Republic of China
| | - Ren-Hao Liu
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi’an Jiaotong University, Xi’an710049, People's Republic of China
| | - Si-Bo Zhou
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi’an Jiaotong University, Xi’an710049, People's Republic of China
| | - Min Zhuo
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi’an Jiaotong University, Xi’an710049, People's Republic of China
- Department of Physiology, Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, OntarioM5S 1A8, Canada
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou325000, People's Republic of China
- Department of Neurology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou510030, People's Republic of China
| |
Collapse
|
|
12
|
Utashiro N, MacLaren DAA, Liu YC, Yaqubi K, Wojak B, Monyer H. Long-range inhibition from prelimbic to cingulate areas of the medial prefrontal cortex enhances network activity and response execution. Nat Commun 2024; 15:5772. [PMID: 38982042 PMCID: PMC11233578 DOI: 10.1038/s41467-024-50055-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 06/28/2024] [Indexed: 07/11/2024] Open
Abstract
It is well established that the medial prefrontal cortex (mPFC) exerts top-down control of many behaviors, but little is known regarding how cross-talk between distinct areas of the mPFC influences top-down signaling. We performed virus-mediated tracing and functional studies in male mice, homing in on GABAergic projections whose axons are located mainly in layer 1 and that connect two areas of the mPFC, namely the prelimbic area (PrL) with the cingulate area 1 and 2 (Cg1/2). We revealed the identity of the targeted neurons that comprise two distinct types of layer 1 GABAergic interneurons, namely single-bouquet cells (SBCs) and neurogliaform cells (NGFs), and propose that this connectivity links GABAergic projection neurons with cortical canonical circuits. In vitro electrophysiological and in vivo calcium imaging studies support the notion that the GABAergic projection neurons from the PrL to the Cg1/2 exert a crucial role in regulating the activity in the target area by disinhibiting layer 5 output neurons. Finally, we demonstrated that recruitment of these projections affects impulsivity and mechanical responsiveness, behaviors which are known to be modulated by Cg1/2 activity.
Collapse
Affiliation(s)
- Nao Utashiro
- Department of Clinical Neurobiology at the Medical Faculty of the Heidelberg University and of the German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Duncan Archibald Allan MacLaren
- Department of Clinical Neurobiology at the Medical Faculty of the Heidelberg University and of the German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Yu-Chao Liu
- Department of Clinical Neurobiology at the Medical Faculty of the Heidelberg University and of the German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Kaneschka Yaqubi
- Department of Clinical Neurobiology at the Medical Faculty of the Heidelberg University and of the German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf and Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Birgit Wojak
- Department of Clinical Neurobiology at the Medical Faculty of the Heidelberg University and of the German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany
| | - Hannah Monyer
- Department of Clinical Neurobiology at the Medical Faculty of the Heidelberg University and of the German Cancer Research Center (DKFZ), Heidelberg, Germany.
| |
Collapse
|
|
13
|
Zacky Ariffin M, Yun Ng S, Nadia H, Koh D, Loh N, Michiko N, Khanna S. Neurokinin1 - cholinergic receptor mechanisms in the medial Septum-Dorsal hippocampus axis mediates experimental neuropathic pain. NEUROBIOLOGY OF PAIN (CAMBRIDGE, MASS.) 2024; 16:100162. [PMID: 39224764 PMCID: PMC11367143 DOI: 10.1016/j.ynpai.2024.100162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 07/23/2024] [Accepted: 07/31/2024] [Indexed: 09/04/2024]
Abstract
The neurokinin-1 receptors (NK1Rs) in the forebrain medial septum (MS) region are localized exclusively on cholinergic neurons that partly project to the hippocampus and the cingulate cortex (Cg), regions implicated in nociception. In the present study, we explored the hypothesis that neurotransmission at septal NK1R and hippocampal cholinergic mechanisms mediate experimental neuropathic pain in the rodent chronic constriction injury model (CCI). Our investigations showed that intraseptal microinjection of substance P (SP) in rat evoked a peripheral hypersensitivity (PH)-like response in uninjured animals that was attenuated by systemic atropine sulphate, a muscarinic-cholinergic receptor antagonist. Conversely, pre-emptive destruction of septal cholinergic neurons attenuated the development of PH in the CCI model that also prevented the expression of cellular markers of nociception in the spinal cord and the forebrain. Likewise, anti-nociception was evoked on intraseptal microinjection of L-733,060, an antagonist at NK1Rs, and on bilateral or unilateral microinjection of the cholinergic receptor antagonists, atropine or mecamylamine, into the different regions of the dorsal hippocampus (dH) or on bilateral microinjection into the Cg. Interestingly, the effect of L-733,060 was accompanied with a widespread decreased in levels of CCI-induced nociceptive cellular markers in forebrain that was not secondary to behaviour, suggesting an active modulation of nociceptive processing by transmission at NK1R in the medial septum. The preceding suggest that the development and maintenance of neuropathic nociception is facilitated by septal NK1R-dH cholinergic mechanisms which co-ordinately affect nociceptive processing in the dH and the Cg. Additionally, the data points to a potential strategy for pain modulation that combines anticholinergics and anti-NKRs.
Collapse
Affiliation(s)
- Mohammed Zacky Ariffin
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Neurobiology Programme, Life Sciences Institute, National University of Singapore, Singapore
| | - Si Yun Ng
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Neurobiology Programme, Life Sciences Institute, National University of Singapore, Singapore
| | - Hamzah Nadia
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Darrel Koh
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Natasha Loh
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Naomi Michiko
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Sanjay Khanna
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Neurobiology Programme, Life Sciences Institute, National University of Singapore, Singapore
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| |
Collapse
|
|
14
|
Chen QY, Wan J, Ma Y, Zhuo M. The Pathway-Selective Dependence of Nitric Oxide for Long-Term Potentiation in the Anterior Cingulate Cortex of Adult Mice. Biomedicines 2024; 12:1072. [PMID: 38791034 PMCID: PMC11118802 DOI: 10.3390/biomedicines12051072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/04/2024] [Accepted: 05/09/2024] [Indexed: 05/26/2024] Open
Abstract
Nitric oxide (NO) is a key diffusible messenger in the mammalian brain. It has been proposed that NO may diffuse in retrograde into presynaptic terminals, contributing to the induction of hippocampal long-term potentiation (LTP). Here, we present novel evidence that NO is selectively required for the synaptic potentiation of the interhemispheric projection in the anterior cingulate cortex (ACC). Unilateral low-frequency stimulation (LFS) induced a short-term synaptic potentiation on the contralateral ACC through the corpus callosum (CC). The use of the antagonists of the NMDA receptor (NMDAR), or the inhibitor of the L-type voltage-dependent Ca2+ channels (L-VDCCs), blocked the induction of this ACC-ACC potentiation. In addition, the inhibitor of NO synthase, or inhibitors for its downstream signaling pathway, also blocked this ACC-ACC potentiation. However, the application of the NOS inhibitor blocked neither the local electric stimulation-induced LTP nor the stimulation-induced recruitment of silent responses. Our results present strong evidence for the pathway-selective roles of NO in the LTP of the ACC.
Collapse
Affiliation(s)
- Qi-Yu Chen
- CAS Key Laboratory of Brain Connectome and Manipulation, Interdisciplinary Center for Brain Information, Chinese Academy of Sciences Shenzhen Institute of Advanced Technology, Shenzhen 518055, China
- Zhuomin International Institute for Brain Research, Qingdao 266000, China
| | - Jinjin Wan
- Zhuomin International Institute for Brain Research, Qingdao 266000, China
- Oujiang Laboratory, Wenzhou Medical University, Wenzhou 325027, China
| | - Yujie Ma
- Zhuomin International Institute for Brain Research, Qingdao 266000, China
- Oujiang Laboratory, Wenzhou Medical University, Wenzhou 325027, China
| | - Min Zhuo
- Zhuomin International Institute for Brain Research, Qingdao 266000, China
- Oujiang Laboratory, Wenzhou Medical University, Wenzhou 325027, China
- Department of Physiology, Faculty of Medicine, University of Toronto, Medical Science Building, Room #3342, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada
| |
Collapse
|
|
15
|
Zhuo M. Cortical synaptic basis of consciousness. Eur J Neurosci 2024; 59:796-806. [PMID: 38013403 DOI: 10.1111/ejn.16198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Accepted: 11/01/2023] [Indexed: 11/29/2023]
Abstract
Consciousness is one of final questions for humans to tackle in neuroscience. Due to a lack of understanding of basic brain networks and mechanisms of functions, our knowledge of consciousness mainly stays at a theoretical level. Recent studies using brain imaging in humans and modern neuroscience techniques in animal studies reveal the basic brain network for consciousness. The projection from the thalamus to different cortical regions forms a network of activities to maintain consciousness in humans and animals. These feedback and feedforward circuits maintain consciousness even in certain brain injury conditions. Pterions and ion channels that contribute to these circuit neural activities are targets for drugs and manipulations that affect consciousness such as anesthetic agents. Synaptic plasticity that trains synapses during learning and information recall modified the circuits and contributes to a high level of consciousness in a certain population.
Collapse
Affiliation(s)
- Min Zhuo
- Department of Pharmacology, Qingdao University School of Pharmacy, Qingdao, China
- Department of Neurology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
16
|
Saby A, Alvarez A, Smolins D, Petros J, Nguyen L, Trujillo M, Aygün O. Effects of Embodiment in Virtual Reality for Treatment of Chronic Pain: Pilot Open-Label Study. JMIR Form Res 2024; 8:e34162. [PMID: 38363591 PMCID: PMC10907942 DOI: 10.2196/34162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 07/13/2022] [Accepted: 09/21/2023] [Indexed: 02/17/2024] Open
Abstract
BACKGROUND Chronic pain has long been a major health burden that has been addressed through numerous forms of pharmacological and nonpharmacological treatment. One of the tenets of modern medicine is to minimize risk while providing efficacy. Further, because of its noninvasive nature, virtual reality (VR) provides an attractive platform for potentially developing novel therapeutic modalities. OBJECTIVE The purpose of this study was to determine the feasibility of a novel VR-based digital therapy for the treatment of chronic pain. METHODS An open-label study assessed the feasibility of using virtual embodiment in VR to treat chronic pain. In total, 24 patients with chronic pain were recruited from local pain clinics and completed 8 sessions of a novel digital therapeutic that combines virtual embodiment with graded motor imagery to deliver functional rehabilitation exercises over the course of 4 weeks. Pain intensity as measured by a visual analog scale before and after each virtual embodiment training session was used as the primary outcome measure. Additionally, a battery of patient-reported pain questionnaires (Fear-Avoidance Beliefs Questionnaire, Oswestry Low Back Pain Disability Questionnaire, Pain Catastrophizing Scale, and Patient Health Questionnaire) were administered before and after 8 sessions of virtual embodiment training as exploratory outcome measures to assess if the measures are appropriate and warrant a larger randomized controlled trial. RESULTS A 2-way ANOVA on session × pre- versus postvirtual embodiment training revealed that individual virtual embodiment training sessions significantly reduced the intensity of pain as measured by the visual analog scale (P<.001). Perceived disability due to lower back pain as measured by the Oswestry Low Back Pain Disability Questionnaire significantly improved (P=.003) over the 4-week course of virtual embodiment regimen. Improvement was also observed on the helplessness subscale of the Pain Catastrophizing Scale (P=.02). CONCLUSIONS This study provides evidence that functional rehabilitation exercises delivered in VR are safe and may have positive effects on alleviating the symptoms of chronic pain. Additionally, the virtual embodiment intervention may improve perceived disability and helplessness of patients with chronic pain after 8 sessions. The results support the justification for a larger randomized controlled trial to assess the extent to which virtual embodiment training can exert an effect on symptoms associated with chronic pain. TRIAL REGISTRATION ClinicalTrials.gov NCT04060875; https://clinicaltrials.gov/ct2/show/NCT04060875.
Collapse
Affiliation(s)
- Adam Saby
- Department of Emergency Medicine, Occupational Health Division, University of California Los Angeles, Los Angeles, CA, United States
| | | | | | - James Petros
- Allied Pain and Spine, San Jose, CA, United States
| | | | | | | |
Collapse
|
|
17
|
Aygün O, Mohr E, Duff C, Matthew S, Schoenberg P. Oxytocin Modulation in Mindfulness-Based Pain Management for Chronic Pain. Life (Basel) 2024; 14:253. [PMID: 38398763 PMCID: PMC10890287 DOI: 10.3390/life14020253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/31/2024] [Accepted: 02/07/2024] [Indexed: 02/25/2024] Open
Abstract
In the context of chronic pain management, opioid-based treatments have been heavily relied upon, raising concerns related to addiction and misuse. Non-pharmacological approaches, such as Mindfulness-Based Pain Management, offer alternative strategies. We conducted a mechanistic clinical study to investigate the impact of an 8-week Mindfulness-Based Pain Management intervention on chronic pain, the modulation of inflammatory markers, stress physiology, and oxytocin, and their interplay with clinical pain symptoms and perception, in comparison to a patient wait-list active control. A total of 65 participants, including 50 chronic pain patients and 15 healthy controls, underwent salivary assays to assess endocrine markers, oxytocin, interleukin (IL)-1b, IL-6, IL-8, tumor necrosis factor (TNF)-a, and dehydroepiandrosterone sulphate (DHEA-S). Psychological assessments were also conducted to evaluate aspects of pain perception, mindfulness, mood, and well-being. Findings revealed significant differences between chronic pain patients and healthy controls in various clinical metrics, highlighting the psychological distress experienced by patients. Following Mindfulness-Based Pain Management, oxytocin levels significantly increased in chronic pain patients, that was not observed in the patient wait-list control group. In contrast, cytokine and DHEA-S levels decreased (not to statistically significant margins) supporting anti-inflammatory effects of Mindfulness-Based Pain Management. The fact DHEA-S levels, a marker of stress, did attenuate but not to statistically meaningful levels, suggests that pain reduction was not solely related to stress reduction, and that oxytocin pathways may be more salient than previously considered. Psychological assessments demonstrated substantial improvements in pain perception and mood in the intervention group. These results contribute to the growing body of evidence regarding the effectiveness of mindfulness-based interventions in chronic pain management and underscore oxytocin's potential role as a therapeutic target.
Collapse
Affiliation(s)
- Oytun Aygün
- Laboratoire DysCo, Université Paris 8 Vincennes-Saint-Denis, 93526 Saint-Denis, France;
| | - Emily Mohr
- Osher Center for Integrative Health, Vanderbilt University Medical Center, Nashville, TN 37203, USA
| | - Colin Duff
- Breathworks Foundation, Manchester M4 1DZ, UK
| | | | - Poppy Schoenberg
- Osher Center for Integrative Health, Vanderbilt University Medical Center, Nashville, TN 37203, USA
| |
Collapse
|
|
18
|
Song Q, Wei A, Xu H, Gu Y, Jiang Y, Dong N, Zheng C, Wang Q, Gao M, Sun S, Duan X, Chen Y, Wang B, Huo J, Yao J, Wu H, Li H, Wu X, Jing Z, Liu X, Yang Y, Hu S, Zhao A, Wang H, Cheng X, Qin Y, Qu Q, Chen T, Zhou Z, Chai Z, Kang X, Wei F, Wang C. An ACC-VTA-ACC positive-feedback loop mediates the persistence of neuropathic pain and emotional consequences. Nat Neurosci 2024; 27:272-285. [PMID: 38172439 DOI: 10.1038/s41593-023-01519-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 11/04/2023] [Indexed: 01/05/2024]
Abstract
The central mechanisms underlying pain chronicity remain elusive. Here, we identify a reciprocal neuronal circuit in mice between the anterior cingulate cortex (ACC) and the ventral tegmental area (VTA) that mediates mutual exacerbation between hyperalgesia and allodynia and their emotional consequences and, thereby, the chronicity of neuropathic pain. ACC glutamatergic neurons (ACCGlu) projecting to the VTA indirectly inhibit dopaminergic neurons (VTADA) by activating local GABAergic interneurons (VTAGABA), and this effect is reinforced after nerve injury. VTADA neurons in turn project to the ACC and synapse to the initial ACCGlu neurons to convey feedback information from emotional changes. Thus, an ACCGlu-VTAGABA-VTADA-ACCGlu positive-feedback loop mediates the progression to and maintenance of persistent pain and comorbid anxiodepressive-like behavior. Disruption of this feedback loop relieves hyperalgesia and anxiodepressive-like behavior in a mouse model of neuropathic pain, both acutely and in the long term.
Collapse
Affiliation(s)
- Qian Song
- Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Core Facilities Sharing Platform, Xi'an Jiaotong University, Xi'an, China
- Department of Neurology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Anqi Wei
- Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Core Facilities Sharing Platform, Xi'an Jiaotong University, Xi'an, China
| | - Huadong Xu
- Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Core Facilities Sharing Platform, Xi'an Jiaotong University, Xi'an, China
- Key Laboratory of Medical Electrophysiology, Ministry of Education of China, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease and the Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Yuhao Gu
- Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Core Facilities Sharing Platform, Xi'an Jiaotong University, Xi'an, China
| | - Yong Jiang
- Department of Neurosurgery, the Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Nan Dong
- Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Core Facilities Sharing Platform, Xi'an Jiaotong University, Xi'an, China
| | - Chaowen Zheng
- Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Core Facilities Sharing Platform, Xi'an Jiaotong University, Xi'an, China
| | - Qinglong Wang
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology; Peking-Tsinghua Center for Life Sciences; and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China
| | - Min Gao
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology; Peking-Tsinghua Center for Life Sciences; and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China
| | - Suhua Sun
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology; Peking-Tsinghua Center for Life Sciences; and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China
| | - Xueting Duan
- Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Core Facilities Sharing Platform, Xi'an Jiaotong University, Xi'an, China
| | - Yang Chen
- Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Core Facilities Sharing Platform, Xi'an Jiaotong University, Xi'an, China
| | - Bianbian Wang
- Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Core Facilities Sharing Platform, Xi'an Jiaotong University, Xi'an, China
| | - Jingxiao Huo
- Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Core Facilities Sharing Platform, Xi'an Jiaotong University, Xi'an, China
| | - Jingyu Yao
- Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Core Facilities Sharing Platform, Xi'an Jiaotong University, Xi'an, China
| | - Hao Wu
- Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Core Facilities Sharing Platform, Xi'an Jiaotong University, Xi'an, China
| | - Hua Li
- Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Core Facilities Sharing Platform, Xi'an Jiaotong University, Xi'an, China
| | - Xuanang Wu
- Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Core Facilities Sharing Platform, Xi'an Jiaotong University, Xi'an, China
| | - Zexin Jing
- Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Core Facilities Sharing Platform, Xi'an Jiaotong University, Xi'an, China
| | - Xiaoying Liu
- Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Core Facilities Sharing Platform, Xi'an Jiaotong University, Xi'an, China
| | - Yuxin Yang
- Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Core Facilities Sharing Platform, Xi'an Jiaotong University, Xi'an, China
- College of Life Sciences, Liaocheng University, Liaocheng, China
| | - Shaoqin Hu
- Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Core Facilities Sharing Platform, Xi'an Jiaotong University, Xi'an, China
| | - Anran Zhao
- Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Core Facilities Sharing Platform, Xi'an Jiaotong University, Xi'an, China
| | - Hongyan Wang
- Key Laboratory of Medical Electrophysiology, Ministry of Education of China, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease and the Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
- College of Life Sciences, Liaocheng University, Liaocheng, China
| | - Xu Cheng
- Key Laboratory of Medical Electrophysiology, Ministry of Education of China, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease and the Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Yuhao Qin
- Key Laboratory of Medical Electrophysiology, Ministry of Education of China, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease and the Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Qiumin Qu
- Department of Neurology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Tao Chen
- Department of Human Anatomy, Histology and Embryology and K.K. Leung Brain Research Centre, the Fourth Military Medical University, Xi'an, China
| | - Zhuan Zhou
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology; Peking-Tsinghua Center for Life Sciences; and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China
| | - Zuying Chai
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Xinjiang Kang
- Key Laboratory of Medical Electrophysiology, Ministry of Education of China, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease and the Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China.
- Department of Neurosurgery, the Affiliated Hospital of Southwest Medical University, Luzhou, China.
- College of Life Sciences, Liaocheng University, Liaocheng, China.
| | - Feng Wei
- Department of Neural and Pain Sciences, School of Dentistry; Program in Neuroscience, Center to Advance Chronic Pain Research, University of Maryland, Baltimore, MD, USA.
| | - Changhe Wang
- Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Core Facilities Sharing Platform, Xi'an Jiaotong University, Xi'an, China.
- Department of Neurology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
- Key Laboratory of Medical Electrophysiology, Ministry of Education of China, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease and the Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China.
- Department of Neurosurgery, the Affiliated Hospital of Southwest Medical University, Luzhou, China.
| |
Collapse
|
|
19
|
Lee J, Jeon S, Kim N, Choi S, Do W, Kim JR, Kim E, Hong JM, Baik J. Effects of Intrathecal Ketamine on Cerebrospinal Fluid Levels of Brain-Derived Neurotrophic Factor and Mechanical Allodynia in a Rat Model of Mild Traumatic Brain Injury. Med Sci Monit 2024; 30:e942574. [PMID: 38297827 PMCID: PMC10845787 DOI: 10.12659/msm.942574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 11/28/2023] [Indexed: 02/02/2024] Open
Abstract
BACKGROUND Ketamine, a compelling candidate for neuropathic pain management, has attracted interest for its potential to elevate brain-derived neurotrophic factor (BDNF) levels. We aimed to assess the effects of intrathecally administered ketamine on the cerebrospinal fluid (CSF) levels of BDNF(c-BDNF) and allodynia in a rat model of traumatic brain injury (TBI). MATERIAL AND METHODS Forty-five rats were divided into 3 groups: sham operation (Group S), untreated TBI (Group T), and ketamine-treated TBI (Group K), with 15 rats in each group. Rats were anesthetized, and their skulls were secured in a stereotactic frame before undergoing craniotomy. A controlled cortical impact (CCI) was induced, followed by injection of ketamine (3.41 µg/g) into the CSF in Group K. In Group T, no drug was injected after CCI delivery. On postoperative days (POD) 1, 7, and 14, the 50% mechanical withdrawal threshold (50% MWT) and c-BDNF levels were assessed. RESULTS Groups T and K exhibited a significantly lower 50% MWT than Group S on POD 1(6.6 [5.7, 8.7] g, 10.0 [6.8, 11.6] g, and 18.7 [11.6, 18.7] g, respectively; P<0.001). The c-BDNF levels in Group K were significantly higher than those in Groups S and T on POD 1 (18.9 [16.1, 23.0] pg/ml, 7.3 [6.0, 8.8] pg/ml, and 11.0 [10.6, 12.3] pg/ml, respectively; P=0.006). CONCLUSIONS Intrathecal ketamine administration did not exhibit anti-allodynic effects following mild TBI. c-BDNF level is a promising potential indicator for predicting the expression of allodynia after mild TBI.
Collapse
Affiliation(s)
- Jiyoun Lee
- Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Soeun Jeon
- Department of Anesthesiology and Pain Medicine, School of Dentistry, Institute for Translational Research in Dentistry, Kyungpook National University, Daegu, South Korea
| | - Nara Kim
- Department of Anesthesia and Pain Medicine, Biomedical Research Institute, Pusan National University Hospital, Busan, South Korea
| | - Sangmin Choi
- Department of Anesthesia and Pain Medicine, Biomedical Research Institute, Pusan National University Hospital, Busan, South Korea
| | - Wangseok Do
- Department of Anesthesia and Pain Medicine, Biomedical Research Institute, Pusan National University Hospital, Busan, South Korea
| | - Jae-Rin Kim
- Pusan National University, School of Medicine, Busan, South Korea
| | - Eunsoo Kim
- Department of Anesthesia and Pain Medicine, Biomedical Research Institute, Pusan National University Hospital, Busan, South Korea
- Pusan National University, School of Medicine, Busan, South Korea
| | - Jeong-Min Hong
- Department of Anesthesia and Pain Medicine, Biomedical Research Institute, Pusan National University Hospital, Busan, South Korea
- Pusan National University, School of Medicine, Busan, South Korea
| | - Jiseok Baik
- Department of Anesthesia and Pain Medicine, Biomedical Research Institute, Pusan National University Hospital, Busan, South Korea
- Pusan National University, School of Medicine, Busan, South Korea
| |
Collapse
|
|
20
|
Zhuo M. Long-term plasticity of NMDA GluN2B (NR2B) receptor in anterior cingulate cortical synapses. Mol Pain 2024; 20:17448069241230258. [PMID: 38246915 PMCID: PMC10851716 DOI: 10.1177/17448069241230258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 01/17/2024] [Accepted: 01/17/2024] [Indexed: 01/23/2024] Open
Abstract
The anterior cingulate cortex (ACC) is a key cortical area for pain perception, emotional fear and anxiety. Cortical excitation is thought to be the major mechanism for chronic pain and its related emotional disorders such as anxiety and depression. GluN2B (or called NR2B) containing NMDA receptors play critical roles for such excitation. Not only does the activation of GluN2B contributes to the induction of the postsynaptic form of LTP (post-LTP), long-term upregulation of GluN2B subunits through tyrosine phosphorylation were also detected after peripheral injury. In addition, it has been reported that presynaptic NMDA receptors may contribute to the modulation of the release of glutamate from presynaptic terminals in the ACC. It is believed that inhibiting subtypes of NMDA receptors and/or downstream signaling proteins may serve as a novel therapeutic mechanism for future treatment of chronic pain, anxiety, and depression.
Collapse
Affiliation(s)
- Min Zhuo
- School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
- Qingdao International Academician Park, Zhuomin Institute of Brain Research, Qingdao, China
- Department of Physiology, University of Toronto, Toronto, ON, Canada
| |
Collapse
|
|
21
|
Mirmoosavi M, Aminitabar A, Mirfathollahi A, Shalchyan V. Exploring altered oscillatory activity in the anterior cingulate cortex after nerve injury: Insights into mechanisms of neuropathic allodynia. Neurobiol Dis 2024; 190:106381. [PMID: 38114049 DOI: 10.1016/j.nbd.2023.106381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/13/2023] [Accepted: 12/13/2023] [Indexed: 12/21/2023] Open
Abstract
While neural oscillations play a critical role in sensory perception, it remains unclear how these rhythms function under conditions of neuropathic allodynia. Recent studies demonstrated that the anterior cingulate cortex (ACC) is associated with the affective-aversive component of pain, and plasticity changes in this region are closely linked to abnormal allodynic sensations. Here, to study the mechanisms of allodynia, we recorded local field potentials (LFPs) in the bilateral ACC of awake-behaving rats and compared the spectral power and center frequency of brain oscillations between healthy and CCI (chronic constriction injury) induced neuropathic pain conditions. Our results indicated that activation of the ACC occurs bilaterally in the presence of neuropathic pain, similar to the healthy condition. Furthermore, CCI affects both spontaneous and stimulus-induced activity of ACC neurons. Specifically, we observed an increase in spontaneous beta activity after nerve injury compared to the healthy condition. By stimulating operated or unoperated paws, we found more intense event-related desynchronization (ERD) responses in the theta, alpha, and beta frequency bands and faster alpha center frequency after CCI compared to before CCI. Although the behavioral manifestation of allodynia was more pronounced in the operated paw than the unoperated paw following CCI, there was no significant difference in the center frequency and ERD responses observed in the ACC between stimulation of the operated and unoperated limbs. Our findings offer evidence supporting the notion that aberrancies in ACC oscillations may contribute to the maintenance and development of neuropathic allodynia.
Collapse
Affiliation(s)
- Mahnoosh Mirmoosavi
- Neuroscience and Neuroengineering Research Lab., Biomedical Engineering Department, School of Electrical Engineering, Iran University of Science and Technology (IUST), Narmak, Tehran 16846-13114, Iran
| | - Amir Aminitabar
- Neuroscience and Neuroengineering Research Lab., Biomedical Engineering Department, School of Electrical Engineering, Iran University of Science and Technology (IUST), Narmak, Tehran 16846-13114, Iran
| | - Alavie Mirfathollahi
- Neuroscience and Neuroengineering Research Lab., Biomedical Engineering Department, School of Electrical Engineering, Iran University of Science and Technology (IUST), Narmak, Tehran 16846-13114, Iran; Institute for Cognitive Science Studies (ICSS), Tehran 16583-44575, Iran
| | - Vahid Shalchyan
- Neuroscience and Neuroengineering Research Lab., Biomedical Engineering Department, School of Electrical Engineering, Iran University of Science and Technology (IUST), Narmak, Tehran 16846-13114, Iran.
| |
Collapse
|
|
22
|
Xi C, He L, Huang Z, Zhang J, Zou K, Guo Q, Huang C. Combined metabolomics and transcriptomics analysis of rats under neuropathic pain and pain-related depression. Front Pharmacol 2023; 14:1320419. [PMID: 38143492 PMCID: PMC10739318 DOI: 10.3389/fphar.2023.1320419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 11/29/2023] [Indexed: 12/26/2023] Open
Abstract
Neuropathic pain often leads to negative emotions, which in turn can enhance the sensation of pain. This study aimed to investigate the molecular mechanisms mediating neuropathic pain and negative emotions. Chronic constriction injury (CCI) rats were used as model animals and behavioral tests were conducted to assess pain and negative emotions. Then, the rat anterior cingulate cortex (ACC) was analyzed using UPLC-MS/MS and subsequently integrated with our previously published transcriptome data. Metabolomics analysis revealed that 68 differentially expressed metabolites (DEMs) were identified, mainly in amino acid metabolites and fatty acyls. Combined with our previously published transcriptome data, we predicted two genes that potentially exhibited associations with these metabolites, respectively Apolipoprotein L domain containing 1 (Apold1) and WAP four-disulfide core domain 1 (Wfdc1). Taken together, our results indicated that peripheral nerve injury contributing to neuropathic pain and pain-related depression may be associated with these metabolites and genes. This research provides new insights into the molecular regulatory mechanism, which could serve as a reference for the treatment of neuropathic pain and pain-related depression.
Collapse
Affiliation(s)
- Caiyun Xi
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, China
| | - Liqiong He
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, China
| | - Zhifeng Huang
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, China
| | - Jianxi Zhang
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, China
| | - Kailu Zou
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, China
| | - Qulian Guo
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Changsheng Huang
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| |
Collapse
|
|
23
|
Xie RG, Xu GY, Wu SX, Luo C. Presynaptic glutamate receptors in nociception. Pharmacol Ther 2023; 251:108539. [PMID: 37783347 DOI: 10.1016/j.pharmthera.2023.108539] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 08/19/2023] [Accepted: 09/25/2023] [Indexed: 10/04/2023]
Abstract
Chronic pain is a frequent, distressing and poorly understood health problem. Plasticity of synaptic transmission in the nociceptive pathways after inflammation or injury is assumed to be an important cellular basis for chronic, pathological pain. Glutamate serves as the main excitatory neurotransmitter at key synapses in the somatosensory nociceptive pathways, in which it acts on both ionotropic and metabotropic glutamate receptors. Although conventionally postsynaptic, compelling anatomical and physiological evidence demonstrates the presence of presynaptic glutamate receptors in the nociceptive pathways. Presynaptic glutamate receptors play crucial roles in nociceptive synaptic transmission and plasticity. They modulate presynaptic neurotransmitter release and synaptic plasticity, which in turn regulates pain sensitization. In this review, we summarize the latest understanding of the expression of presynaptic glutamate receptors in the nociceptive pathways, and how they contribute to nociceptive information processing and pain hypersensitivity associated with inflammation / injury. We uncover the cellular and molecular mechanisms of presynaptic glutamate receptors in shaping synaptic transmission and plasticity to mediate pain chronicity, which may provide therapeutic approaches for treatment of chronic pain.
Collapse
Affiliation(s)
- Rou-Gang Xie
- Department of Neurobiology, Fourth Military Medical University, Xi'an 710032, China.
| | - Guang-Yin Xu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Institute of Neuroscience, Soochow University, Suzhou 215123, China
| | - Sheng-Xi Wu
- Department of Neurobiology, Fourth Military Medical University, Xi'an 710032, China.
| | - Ceng Luo
- Department of Neurobiology, Fourth Military Medical University, Xi'an 710032, China.
| |
Collapse
|
|
24
|
Wang TZ, Wang F, Tian ZC, Li ZZ, Liu WN, Ding H, Xie TT, Cao ZX, Li HT, Sun ZC, Xie RG, Wu SX, Pan ZX, Luo C. Cingulate cGMP-dependent protein kinase I facilitates chronic pain and pain-related anxiety and depression. Pain 2023; 164:2447-2462. [PMID: 37326662 DOI: 10.1097/j.pain.0000000000002952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 04/25/2023] [Indexed: 06/17/2023]
Abstract
ABSTRACT Patients with chronic pain often experience exaggerated pain response and aversive emotion, such as anxiety and depression. Central plasticity in the anterior cingulate cortex (ACC) is assumed to be a critical interface for pain perception and emotion, which has been reported to involve activation of NMDA receptors. Numerous studies have documented the key significance of cGMP-dependent protein kinase I (PKG-I) as a crucial downstream target for the NMDA receptor-NO-cGMP signaling cascade in regulating neuronal plasticity and pain hypersensitivity in specific regions of pain pathway, ie, dorsal root ganglion or spinal dorsal horn. Despite this, whether and how PKG-I in the ACC contributes to cingulate plasticity and comorbidity of chronic pain and aversive emotion has remained elusive. Here, we uncovered a crucial role of cingulate PKG-I in chronic pain and comorbid anxiety and depression. Chronic pain caused by tissue inflammation or nerve injury led to upregulation of PKG-I expression at both mRNA and protein levels in the ACC. Knockdown of ACC-PKG-I relieved pain hypersensitivity as well as pain-associated anxiety and depression. Further mechanistic analysis revealed that PKG-I might act to phosphorylate TRPC3 and TRPC6, leading to enhancement of calcium influx and neuronal hyperexcitability as well as synaptic potentiation, which results in the exaggerated pain response and comorbid anxiety and depression. We believe this study sheds new light on the functional capability of ACC-PKG-I in modulating chronic pain as well as pain-associated anxiety and depression. Hence, cingulate PKG-I may represent a new therapeutic target against chronic pain and pain-related anxiety and depression.
Collapse
Affiliation(s)
- Tao-Zhi Wang
- Department of Anesthesiology, The Second Hospital of Jilin University, Jilin University, Changchun, China
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China
| | - Fei Wang
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China
- Medical Experiment Center, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Zhi-Cheng Tian
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Zhen-Zhen Li
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China
| | - Wan-Neng Liu
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China
- College of Life Sciences, Northwest University, Xi'an, China
| | - Hui Ding
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China
| | - Ting-Ting Xie
- Department of Anesthesiology, The Second Hospital of Jilin University, Jilin University, Changchun, China
| | - Zi-Xuan Cao
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China
- The Twenty-second Squadron of the Sixth Regiment, School of Basal Medicine, Fourth Military Medical University, Xi'an, China
| | - Hai-Tao Li
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China
- The Fourteenth Squadron of the Fourth Regiment, School of Basal Medicine, Fourth Military Medical University, Xi'an, China
| | - Zhi-Chuan Sun
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China
- Department of Neurosurgery, Xi'an Daxing Hospital, Xi'an, China
| | - Rou-Gang Xie
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China
| | - Sheng-Xi Wu
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China
| | - Zhen-Xiang Pan
- Department of Anesthesiology, The Second Hospital of Jilin University, Jilin University, Changchun, China
| | - Ceng Luo
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China
| |
Collapse
|
|
25
|
Song XJ, Yang CL, Chen D, Yang Y, Mao Y, Cao P, Jiang A, Wang W, Zhang Z, Tao W. Up-regulation of LCN2 in the anterior cingulate cortex contributes to neural injury-induced chronic pain. Front Cell Neurosci 2023; 17:1140769. [PMID: 37362002 PMCID: PMC10285483 DOI: 10.3389/fncel.2023.1140769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 05/02/2023] [Indexed: 06/28/2023] Open
Abstract
Chronic pain caused by disease or injury affects more than 30% of the general population. The molecular and cellular mechanisms underpinning the development of chronic pain remain unclear, resulting in scant effective treatments. Here, we combined electrophysiological recording, in vivo two-photon (2P) calcium imaging, fiber photometry, Western blotting, and chemogenetic methods to define a role for the secreted pro-inflammatory factor, Lipocalin-2 (LCN2), in chronic pain development in mice with spared nerve injury (SNI). We found that LCN2 expression was upregulated in the anterior cingulate cortex (ACC) at 14 days after SNI, resulting in hyperactivity of ACC glutamatergic neurons (ACCGlu) and pain sensitization. By contrast, suppressing LCN2 protein levels in the ACC with viral constructs or exogenous application of neutralizing antibodies leads to significant attenuation of chronic pain by preventing ACCGlu neuronal hyperactivity in SNI 2W mice. In addition, administering purified recombinant LCN2 protein in the ACC could induce pain sensitization by inducing ACCGlu neuronal hyperactivity in naïve mice. This study provides a mechanism by which LCN2-mediated hyperactivity of ACCGlu neurons contributes to pain sensitization, and reveals a new potential target for treating chronic pain.
Collapse
Affiliation(s)
- Xiang-Jie Song
- Hefei National Research Center for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Chen-Ling Yang
- Key Laboratory of Oral Diseases Research of Anhui Province, College and Hospital of Stomatology, Anhui Medical University, Hefei, China
- Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Danyang Chen
- Hefei National Research Center for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yumeng Yang
- Key Laboratory of Oral Diseases Research of Anhui Province, College and Hospital of Stomatology, Anhui Medical University, Hefei, China
- Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Yu Mao
- Hefei National Research Center for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Peng Cao
- Department of Neurology, Stroke Center, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Aijun Jiang
- Department of Endocrinology and Laboratory for Diabetes, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Wei Wang
- Department of Endocrinology and Laboratory for Diabetes, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Zhi Zhang
- Hefei National Research Center for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Wenjuan Tao
- Key Laboratory of Oral Diseases Research of Anhui Province, College and Hospital of Stomatology, Anhui Medical University, Hefei, China
- Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| |
Collapse
|
|
26
|
Hao S, Shi W, Liu W, Chen QY, Zhuo M. Multiple modulatory roles of serotonin in chronic pain and injury-related anxiety. Front Synaptic Neurosci 2023; 15:1122381. [PMID: 37143481 PMCID: PMC10151796 DOI: 10.3389/fnsyn.2023.1122381] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 04/03/2023] [Indexed: 05/06/2023] Open
Abstract
Chronic pain is long-lasting pain that often persists during chronic diseases or after recovery from disease or injury. It often causes serious side effects, such as insomnia, anxiety, or depression which negatively impacts the patient's overall quality of life. Serotonin (5-HT) in the central nervous system (CNS) has been recognized as an important neurotransmitter and neuromodulator which regulates various physiological functions, such as pain sensation, cognition, and emotions-especially anxiety and depression. Its widespread and diverse receptors underlie the functional complexity of 5-HT in the CNS. Recent studies found that both chronic pain and anxiety are associated with synaptic plasticity in the anterior cingulate cortex (ACC), the insular cortex (IC), and the spinal cord. 5-HT exerts multiple modulations of synaptic transmission and plasticity in the ACC and the spinal cord, including activation, inhibition, and biphasic actions. In this review, we will discuss the multiple actions of the 5-HT system in both chronic pain and injury-related anxiety, and the synaptic mechanisms behind them. It is likely that the specific 5-HT receptors would be new promising therapeutic targets for the effective treatment of chronic pain and injury-related anxiety in the future.
Collapse
Affiliation(s)
- Shun Hao
- Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, Shandong, China
- Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou, Zhejiang, China
- International Institute of Brain Research, Forevercheer Medicine Pharmac Inc., Qingdao, Shandong, China
| | - Wantong Shi
- Center for Neuron and Disease, Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Weiqi Liu
- Center for Neuron and Disease, Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Qi-Yu Chen
- International Institute of Brain Research, Forevercheer Medicine Pharmac Inc., Qingdao, Shandong, China
- The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China
| | - Min Zhuo
- Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, Shandong, China
- Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou, Zhejiang, China
- International Institute of Brain Research, Forevercheer Medicine Pharmac Inc., Qingdao, Shandong, China
- Center for Neuron and Disease, Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| |
Collapse
|
|
27
|
Lavorini F, Bernacchi G, Fumagalli C, Noale M, Maggi S, Mutolo D, Cinelli E, Fontana GA. Somatically evoked cough responses help to identify patients with difficult-to-treat chronic cough: a six-month observational cohort study. EClinicalMedicine 2023; 57:101869. [PMID: 36874394 PMCID: PMC9975680 DOI: 10.1016/j.eclinm.2023.101869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 01/23/2023] [Accepted: 01/30/2023] [Indexed: 02/22/2023] Open
Abstract
BACKGROUND Recently we identified in patients with chronic cough a sensory dysregulation via which the urge-to-cough (UTC) or coughing are evoked mechanically from "somatic points for cough" (SPCs) in the neck and upper trunk. We investigated the prevalence and the clinical relevance of SPCs in an unselected population of patients with chronic cough. METHODS From 2018 to 2021, symptoms of 317 consecutive patients with chronic cough (233 females) were collected on four visits (V1-V4) 2 months apart at the Cough Clinic of the University Hospital in Florence (I). Participants rated the disturbance caused by the cough (0-9 modified Borg Scale). We attempted to evoke coughing and/or UTC using mechanical actions in all participants who were subsequently categorised as responsive (somatic point for cough positive, SPC+) or unresponsive (SPC-) to these actions. An association was established between chronic cough and its commonest causes; treatments were administered accordingly. FINDINGS 169 patients were SPC+ and had a higher baseline cough score (p < 0.01). In most of the patients, the treatments reduced (p < 0.01) cough-associated symptoms. All patients reported a decrease (p < 0.01) in cough score at V2 (from 5.70 ± 1.4 to 3.43 ± 1.9 and from 5.01 ± 1.5 to 2.74 ± 1.7 for SPC+ and SPC- patients respectively). However, whilst in SPC- patients the cough score continued to decrease indicating virtually complete cough disappearance at V4 (0.97 ± 0.8), in SPC+ patients this variable remained close to V2 values during the entire follow-up. INTERPRETATION Our study suggests that the assessment of SPCs may identify patients whose cough is unresponsive and are eligible for specific treatments. FUNDING This work was funded by an unrestricted grant from Merck (Italy).
Collapse
Affiliation(s)
- Federico Lavorini
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
- Corresponding author. Department of Experimental and Clinical Medicine, Largo Brambilla 3, Florence 50134, Italy.
| | - Guja Bernacchi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Carlo Fumagalli
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Marianna Noale
- Italian National Research Council (CNR), Neuroscience Institute, Aging Branch, Padua, Italy
| | - Stefania Maggi
- Italian National Research Council (CNR), Neuroscience Institute, Aging Branch, Padua, Italy
| | - Donatella Mutolo
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Eliana Cinelli
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Giovanni A. Fontana
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| |
Collapse
|
|
28
|
Ambron R. Toward the unknown: consciousness and pain. Neurosci Conscious 2023; 2023:niad002. [PMID: 36814785 PMCID: PMC9940454 DOI: 10.1093/nc/niad002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 12/12/2022] [Accepted: 01/15/2023] [Indexed: 02/22/2023] Open
Abstract
Studies of consciousness are hindered by the complexity of the brain, but it is possible to study the consciousness of a sensation, namely pain. Three systems are necessary to experience pain: the somatosensory system conveys information about an injury to the thalamus where an awareness of the injury but not the painfulness emerges. The thalamus distributes the information to the affective system, which modulates the intensity of the pain, and to the cognitive system that imparts attention to the pain. Imaging of patients in pain and those experiencing placebo and hypnosis-induced analgesia shows that two essential cortical circuits for pain and attention are located within the anterior cingulate cortex. The circuits are activated when a high-frequency input results in the development of a long-term potentiation (LTP) at synapses on the apical dendrites of pyramidal neurons. The LTP acts via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors, and an anterior cingulate cortex-specific type-1 adenylate cyclase is necessary for both the LTP and the pain. The apical dendrites form an extensive network such that the input from serious injuries results in the emergence of a local field potential. Using mouse models, I propose experiments designed to test the hypothesis that the local field potential is necessary and sufficient for the consciousness of pain.
Collapse
Affiliation(s)
- Richard Ambron
- *Correspondence address. Department of Cell Biology and Pathology, Vagelos College of Physicians and Surgeons, Columbia University, 320 East Shore Road, Apt. 7C, Great Neck, New York, NY 11023, USA. Tel: +516-244-4530; E-mail: , E-mail:
| |
Collapse
|
|
29
|
Zamorano AM, Kleber B, Arguissain F, Vuust P, Flor H, Graven-Nielsen T. Extensive sensorimotor training enhances nociceptive cortical responses in healthy individuals. Eur J Pain 2023; 27:257-277. [PMID: 36394423 PMCID: PMC10107321 DOI: 10.1002/ejp.2057] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 11/04/2022] [Accepted: 11/13/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND Prolonged and repeated sensorimotor training is a crucial driver for promoting use-dependent plasticity, but also a main risk factor for developing musculoskeletal pain syndromes, yet the neural underpinnings that link repetitive movements to abnormal pain processing are unknown. METHODS Twenty healthy musicians, one of the best in vivo models to study use-dependent plasticity, and 20 healthy non-musicians were recruited. Perceptual thresholds, reaction times (RTs) and event-related potentials (ERPs) were recorded using nociceptive intra-epidermal and non-nociceptive transcutaneous electrical stimulation. RESULTS In response to comparable stimulus intensities, musicians compared to non-musicians showed larger non-nociceptive N140 (associated with higher activation of regions within the salience network), higher nociceptive N200 ERPs (associated with higher activation of regions within the sensorimotor network) and faster RTs to both stimuli. Non-musicians showed larger non-nociceptive P200 ERP. Notably, a similar P200 component prominently emerged during nociceptive stimulation in non-musicians. Across participants, larger N140 and N200 ERPs were associated with RTs, whereas the amount of daily practice in musicians explained non-nociceptive P200 and nociceptive P300 ERPs. CONCLUSIONS These novel findings indicate that the mechanisms by which extensive sensorimotor training promotes use-dependent plasticity in multisensory neural structures may also shape the neural signatures of nociceptive processing in healthy individuals. SIGNIFICANCE Repetitive sensorimotor training may increase the responsiveness of nociceptive evoked potentials. These novel data highlight the importance of repetitive sensorimotor practice as a contributing factor to the interindividual variability of nociceptive-related potentials.
Collapse
Affiliation(s)
- Anna M Zamorano
- Center for Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
| | - Boris Kleber
- Center for Music in the Brain, Dept. of Clinical Medicine, Aarhus University & The Royal Academy of Music Aarhus/Aalborg, Aarhus and Aalborg, Denmark
| | - Federico Arguissain
- Center for Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
| | - Peter Vuust
- Center for Music in the Brain, Dept. of Clinical Medicine, Aarhus University & The Royal Academy of Music Aarhus/Aalborg, Aarhus and Aalborg, Denmark
| | - Herta Flor
- Center for Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
- Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Thomas Graven-Nielsen
- Center for Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
| |
Collapse
|
|
30
|
Decreased ALFF and Functional Connectivity of the Thalamus in Vestibular Migraine Patients. Brain Sci 2023; 13:brainsci13020183. [PMID: 36831726 PMCID: PMC9954115 DOI: 10.3390/brainsci13020183] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/14/2023] [Accepted: 01/19/2023] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND The thalamus has been reported to be associated with pain modulation and processing. However, the functional changes that occur in the thalamus of vestibular migraine (VM) patients remain unknown. METHODS In total, 28 VM patients and 28 healthy controls who were matched for age and sex underwent resting-state functional magnetic resonance imaging. They also responded to standardized questionnaires aimed at assessing the clinical features associated with migraine and vertigo. Differences in the amplitude of low-frequency fluctuation (ALFF) were analyzed and brain regions with altered ALFF in the two groups were used for further analysis of whole-brain functional connectivity (FC). The relationship between clusters and clinical features was investigated by correlation analyses. RESULTS The ALFF in the thalamus was significantly decreased in the VM group versus the control group. In the VM group, the ALFF in the left thalamus negatively correlated with VM episode frequency. Furthermore, the left thalamus showed significantly weaker FC than both regions of the medial prefrontal cortex, both regions of the anterior cingulum cortex, the left superior/middle temporal gyrus, and the left temporal pole in the VM group. CONCLUSIONS The thalamus plays an important role in VM patients and it is suggested that connectivity abnormalities of the thalamocortical region contribute to abnormal pain information processing and modulation, transmission, and multisensory integration in patients with VM.
Collapse
|
|
31
|
Lee JHA, Chen Q, Zhuo M. Synaptic Plasticity in the Pain-Related Cingulate and Insular Cortex. Biomedicines 2022; 10:2745. [PMID: 36359264 PMCID: PMC9687873 DOI: 10.3390/biomedicines10112745] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/14/2022] [Accepted: 10/22/2022] [Indexed: 09/23/2023] Open
Abstract
Cumulative animal and human studies have consistently demonstrated that two major cortical regions in the brain, namely the anterior cingulate cortex (ACC) and insular cortex (IC), play critical roles in pain perception and chronic pain. Neuronal synapses in these cortical regions of adult animals are highly plastic and can undergo long-term potentiation (LTP), a phenomenon that is also reported in brain areas for learning and memory (such as the hippocampus). Genetic and pharmacological studies show that inhibiting such cortical LTP can help to reduce behavioral sensitization caused by injury as well as injury-induced emotional changes. In this review, we will summarize recent progress related to synaptic mechanisms for different forms of cortical LTP and their possible contribution to behavioral pain and emotional changes.
Collapse
Affiliation(s)
- Jung-Hyun Alex Lee
- Department of Physiology, Faculty of Medicine, University of Toronto, Medical Science Building, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada
| | - Qiyu Chen
- Institute of Brain Research, Qingdao International Academician Park, Qingdao 266199, China
- Center for Neuron and Disease, Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China
| | - Min Zhuo
- Department of Physiology, Faculty of Medicine, University of Toronto, Medical Science Building, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada
- Institute of Brain Research, Qingdao International Academician Park, Qingdao 266199, China
- Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou 325000, China
| |
Collapse
|
|
32
|
Xu QY, Zhang HL, Du H, Li YC, Ji FH, Li R, Xu GY. Identification of a Glutamatergic Claustrum-Anterior Cingulate Cortex Circuit for Visceral Pain Processing. J Neurosci 2022; 42:8154-8168. [PMID: 36100399 PMCID: PMC9637003 DOI: 10.1523/jneurosci.0779-22.2022] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 08/30/2022] [Accepted: 09/04/2022] [Indexed: 11/21/2022] Open
Abstract
Chronic visceral pain is a major challenge for both patients and health providers. Although the central sensitization of the brain is thought to play an important role in the development of visceral pain, the detailed neural circuits remain largely unknown. Using a well-established chronic visceral hypersensitivity model induced by neonatal maternal deprivation (NMD) in male mice, we identified a distinct pathway whereby the claustrum (CL) glutamatergic neuron projecting to the anterior cingulate cortex (ACC) is critical for visceral pain but not for CFA-evoked inflammatory pain. By a combination of in vivo circuit-dissecting extracellular electrophysiological approaches and visceral pain related electromyographic (EMG) recordings, we demonstrated that optogenetic inhibition of CL glutamatergic activity suppressed the ACC neural activity and visceral hypersensitivity of NMD mice whereas selective activation of CL glutamatergic activity enhanced the ACC neural activity and evoked visceral pain of control mice. Further, optogenetic studies demonstrate a causal link between such neuronal activity and visceral pain behaviors. Chemogenetic activation or inhibition of ACC neural activities reversed the effects of optogenetic manipulation of CL neural activities on visceral pain responses. Importantly, molecular detection showed that NMD significantly enhances the expression of NMDA receptors and activated CaMKIIα in the ACC postsynaptic density (PSD) region. Together, our data establish a functional role for CL→ACC glutamatergic neurons in gating visceral pain, thus providing a potential treatment strategy for visceral pain.SIGNIFICANCE STATEMENT Studies have shown that sensitization of anterior cingulate cortex (ACC) plays an important role in chronic pain. However, it is as yet unknown whether there is a specific brain region and a distinct neural circuit that helps the ACC to distinguish visceral and somatic pain. The present study demonstrates that claustrum (CL) glutamatergic neurons maybe responding to colorectal distention (CRD) rather than somatic stimulation and that a CL glutamatergic projection to ACC glutamatergic neuron regulates visceral pain in mice. Furthermore, excessive NMDA receptors and overactive CaMKIIα in the ACC postsynaptic density (PSD) region were observed in mice with chronic visceral pain. Together, these findings reveal a novel neural circuity underlying the central sensitization of chronic visceral pain.
Collapse
Affiliation(s)
- Qi-Ya Xu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Institute of Neuroscience, Soochow University, Suzhou 215123, People's Republic of China
| | - Hai-Long Zhang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Institute of Neuroscience, Soochow University, Suzhou 215123, People's Republic of China
| | - Han Du
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Institute of Neuroscience, Soochow University, Suzhou 215123, People's Republic of China
| | - Yong-Chang Li
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Institute of Neuroscience, Soochow University, Suzhou 215123, People's Republic of China
| | - Fu-Hai Ji
- Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, People's Republic of China
| | - Rui Li
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou 215006, People's Republic of China
| | - Guang-Yin Xu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Institute of Neuroscience, Soochow University, Suzhou 215123, People's Republic of China
| |
Collapse
|
|
33
|
Liu YJ, Li YL, Fang ZH, Liao HL, Zhang YY, Lin J, Liu F, Shen JF. NMDARs mediate peripheral and central sensitization contributing to chronic orofacial pain. Front Cell Neurosci 2022; 16:999509. [PMID: 36238833 PMCID: PMC9553029 DOI: 10.3389/fncel.2022.999509] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 08/22/2022] [Indexed: 11/28/2022] Open
Abstract
Peripheral and central sensitizations of the trigeminal nervous system are the main mechanisms to promote the development and maintenance of chronic orofacial pain characterized by allodynia, hyperalgesia, and ectopic pain after trigeminal nerve injury or inflammation. Although the pathomechanisms of chronic orofacial pain are complex and not well known, sufficient clinical and preclinical evidence supports the contribution of the N-methyl-D-aspartate receptors (NMDARs, a subclass of ionotropic glutamate receptors) to the trigeminal nociceptive signal processing pathway under various pathological conditions. NMDARs not only have been implicated as a potential mediator of pain-related neuroplasticity in the peripheral nervous system (PNS) but also mediate excitatory synaptic transmission and synaptic plasticity in the central nervous system (CNS). In this review, we focus on the pivotal roles and mechanisms of NMDARs in the trigeminal nervous system under orofacial neuropathic and inflammatory pain. In particular, we summarize the types, components, and distribution of NMDARs in the trigeminal nervous system. Besides, we discuss the regulatory roles of neuron-nonneuronal cell/neuron-neuron communication mediated by NMDARs in the peripheral mechanisms of chronic orofacial pain following neuropathic injury and inflammation. Furthermore, we review the functional roles and mechanisms of NMDARs in the ascending and descending circuits under orofacial neuropathic and inflammatory pain conditions, which contribute to the central sensitization. These findings are not only relevant to understanding the underlying mechanisms, but also shed new light on the targeted therapy of chronic orofacial pain.
Collapse
Affiliation(s)
- Ya-Jing Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, National Center for Stomatology, West China School of Stomatology, Sichuan University, Chengdu, China
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yue-Ling Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, National Center for Stomatology, West China School of Stomatology, Sichuan University, Chengdu, China
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zhong-Han Fang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, National Center for Stomatology, West China School of Stomatology, Sichuan University, Chengdu, China
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Hong-Lin Liao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, National Center for Stomatology, West China School of Stomatology, Sichuan University, Chengdu, China
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yan-Yan Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, National Center for Stomatology, West China School of Stomatology, Sichuan University, Chengdu, China
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jiu Lin
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, National Center for Stomatology, West China School of Stomatology, Sichuan University, Chengdu, China
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Fei Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, National Center for Stomatology, West China School of Stomatology, Sichuan University, Chengdu, China
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- *Correspondence: Jie-Fei Shen Fei Liu
| | - Jie-Fei Shen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, National Center for Stomatology, West China School of Stomatology, Sichuan University, Chengdu, China
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- *Correspondence: Jie-Fei Shen Fei Liu
| |
Collapse
|
|
34
|
Low-Intensity Focused Ultrasound Alleviates Chronic Neuropathic Pain-Induced Allodynia by Inhibiting Neuroplasticity in the Anterior Cingulate Cortex. Neural Plast 2022; 2022:6472475. [PMID: 35915650 PMCID: PMC9338851 DOI: 10.1155/2022/6472475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 06/13/2022] [Accepted: 07/07/2022] [Indexed: 11/17/2022] Open
Abstract
Low-intensity focused ultrasound (LIFU) is a potential noninvasive method to alleviate allodynia by modulating the central nervous system. However, the underlying analgesic mechanisms remain unexplored. Here, we assessed how LIFU at the anterior cingulate cortex (ACC) affects behavior response and central plasticity resulting from chronic constrictive injury (CCI). The safety of LIFU stimulation was assessed by hematoxylin and eosin (H&E) and Fluoro-Jade C (FJC) staining. A 21-day ultrasound exposure therapy was conducted from day 91 after CCI surgery in mice. We assessed the 50% mechanical withdrawal threshold (MWT50) using Von Frey filaments (VFFs). The expression levels of microtubule-associated protein 2 (MAP2), growth-associated protein 43 (GAP43), and tau were determined via western blotting (WB) and immunofluorescence (IF) staining to evaluate the central plasticity in ACC. The regions of ACC were activated effectively and safely by LIFU stimulation, which significantly increased the number of c-fos-positive cells (P < 0.05) with no bleeding, coagulative necrosis, and neuronal loss. Under chronic neuropathic pain- (CNP-) induced allodynia, MWT50 decreased significantly (P < 0.05), and overexpression of MAP2, GAP43, and tau was also observed. After 3 weeks of treatment, significant increases in MWT50 were found in the CCI+LIFU group compared with the CCI group (P < 0.05). WB and IF staining both demonstrated a significant reduction in the expression levels of MAP2, GAP43, and tau (P < 0.05). LIFU treatment on ACC can effectively attenuate CNP-evoked mechanical sensitivity to pain and reverse aberrant central plasticity.
Collapse
|
|
35
|
Multi-Region Local Field Potential Signatures in Response to the Formalin-induced Inflammatory Stimulus in Male Rats. Brain Res 2022; 1778:147779. [PMID: 35007546 DOI: 10.1016/j.brainres.2022.147779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 12/31/2021] [Accepted: 01/03/2022] [Indexed: 11/22/2022]
Abstract
Pain can be ignited by noxious chemical (e.g., acid), mechanical (e.g., pressure), and thermal (e.g., heat) stimuli and generated by the activation of sensory neurons and their axonal terminals called nociceptors in the periphery. Nociceptive information transmitted from the periphery is projected to the central nervous system (thalamus, somatosensory cortex, insular, anterior cingulate cortex, amygdala, periaqueductal grey, prefrontal cortex, etc.) to generate a unified experience of pain. Local field potential (LFP) recording is one of the neurophysiological tools to investigate the combined neuronal activity, ranging from several hundred micrometers to a few millimeters (radius), located around the embedded electrode. The advantage of recording LFP is that it provides stable simultaneous activities in various brain regions in response to external stimuli. In this study, differential LFP activities from the contralateral anterior cingulate cortex (ACC), ventral tegmental area (VTA), and bilateral amygdala in response to peripheral noxious formalin injection were recorded in anesthetized male rats. The results indicated increased power of delta, theta, alpha, beta, and gamma bands in the ACC and amygdala but no change of gamma-band in the right amygdala. Within the VTA, intensities of the delta, theta, and beta bands were only enhanced significantly after formalin injection. It was found that the connectivity (i.t. the coherence) among these brain regions reduced significantly under the formalin-induced nociception, which suggests a significant interruption within the brain. With further study, it will sort out the key combination of structures that will serve as the signature for pain state.
Collapse
|
|
36
|
Gray matter volume reduction with different disease duration in trigeminal neuralgia. Neuroradiology 2022; 64:301-311. [PMID: 34453181 PMCID: PMC8397610 DOI: 10.1007/s00234-021-02783-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Accepted: 07/30/2021] [Indexed: 02/07/2023]
Abstract
PURPOSE Structural magnetic resonance imaging is widely used to explore brain gray and white matter structure in trigeminal neuralgia (TN) but has yielded conflicting findings. This study investigated the relationship between disease duration as a clinical feature of TN and changes in brain structure. METHODS We divided 49 TN patients into three groups (TN1-TN3) based on disease duration (TN1 = 1.1 ± 0.7 (0-2) years, TN2 = 4.8 ± 1.5 (3-7) years, TN3 = 15.1 ± 5.5 (10-30) years). We used voxel-based morphometry (VBM) to compare the gray matter volume (GMV) across groups and between TN patients and 18 matched healthy control subjects. RESULTS The TN1 group showed reduced GMV of pain-related regions in the cerebellum; the TN2 group showed reduced GMV in the thalamus and the motor/sensory cortex; and the TN3 group showed reduced GMV in the emotional and reward circuits compared with healthy controls. Similar brain regions, including bilateral hippocampi, caudate, left insular cortex, and medial superior frontal cortex, were affected in TN2 and TN3 compared with TN1. CONCLUSION Disease duration can explain differences in structural alterations-especially in pain-related brain regions-in TN. These results highlight the advanced structural neuroimaging method that are valuable tools to assess the trigeminal system in TN and may further our current understanding of TN pathology.
Collapse
|
|
37
|
Zhou Z, Ye P, Li XH, Zhang Y, Li M, Chen QY, Lu JS, Xue M, Li Y, Liu W, Lu L, Shi W, Xu PY, Zhuo M. Synaptic potentiation of anterior cingulate cortex contributes to chronic pain of Parkinson's disease. Mol Brain 2021; 14:161. [PMID: 34742316 PMCID: PMC8572509 DOI: 10.1186/s13041-021-00870-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 10/18/2021] [Indexed: 11/22/2022] Open
Abstract
Parkinson’s disease (PD) is a multi-system neurodegenerative disorder. Patients with PD often suffer chronic pain. In the present study, we investigated motor, sensory and emotional changes in three different PD mice models. We found that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treatment caused significant changes in all measurements. Mechanical hypersensitivity of PD model induced by MPTP peaked at 3 days and persisted for at least 14 days. Using Fos transgenic mice, we found that neurons in the anterior cingulate cortex (ACC) were activated after MPTP treatment. Inhibiting ACC by bilateral microinjection of muscimol significantly reduced mechanical hypersensitivity and anxiety-like responses. By contrast, MPTP induced motor deficit was not affected, indicating ACC activity is mostly responsible for sensory and emotional changes. We also investigated excitatory synaptic transmission and plasticity using brain slices of MPTP treated animals. While L-LTP was blocked or significantly reduced. E-LTP was not significantly affected in slices of MPTP treated animals. LTD induced by repetitive stimulation was not affected. Furthermore, we found that paired-pulse facilitation and spontaneous release of glutamate were also altered in MPTP treated animals, suggesting presynaptic enhancement of excitatory transmission in PD. Our results suggest that ACC synaptic transmission is enhanced in the animal model of PD, and cortical excitation may play important roles in PD related pain and anxiety.
Collapse
Affiliation(s)
- Zhaoxiang Zhou
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Penghai Ye
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xu-Hui Li
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.,Institute of Brain Research, Qingdao International Academician Park, Qingdao, Shandong, China
| | - Yuxiang Zhang
- Institute of Brain Research, Qingdao International Academician Park, Qingdao, Shandong, China
| | - Muhang Li
- Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Tokyo, Japan
| | - Qi-Yu Chen
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.,Institute of Brain Research, Qingdao International Academician Park, Qingdao, Shandong, China
| | - Jing-Shan Lu
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.,Institute of Brain Research, Qingdao International Academician Park, Qingdao, Shandong, China
| | - Man Xue
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Yanan Li
- Institute of Brain Research, Qingdao International Academician Park, Qingdao, Shandong, China
| | - Weiqi Liu
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Lin Lu
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wantong Shi
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Ping-Yi Xu
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
| | - Min Zhuo
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China. .,Institute of Brain Research, Qingdao International Academician Park, Qingdao, Shandong, China. .,Department of Physiology, Faculty of Medicine, University of Toronto, Medical Science Building, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
| |
Collapse
|
|
38
|
Miao HH, Miao Z, Pan JG, Li XH, Zhuo M. Brain-derived neurotrophic factor produced long-term synaptic enhancement in the anterior cingulate cortex of adult mice. Mol Brain 2021; 14:140. [PMID: 34526080 PMCID: PMC8442386 DOI: 10.1186/s13041-021-00853-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 09/04/2021] [Indexed: 12/04/2022] Open
Abstract
Previous studies have demonstrated that brain-derived neurotrophic factor (BDNF) is one of the diffusible messengers for enhancing synaptic transmission in the hippocampus. Less information is available about the possible roles of BDNF in the anterior cingulate cortex (ACC). In the present study, we used 64-electrode array field recording system to investigate the effect of BDNF on ACC excitatory transmission. We found that BDNF enhanced synaptic responses in a dose-dependent manner in the ACC in C57/BL6 mice. The enhancement was long-lasting, and persisted for at least 3 h. In addition to the enhancement, BDNF also recruited inactive synaptic responses in the ACC. Bath application of the tropomyosin receptor kinase B (TrkB) receptor antagonist K252a blocked BDNF-induced enhancement. L-type voltage-gated calcium channels (L-VGCC), metabotropic glutamate receptors (mGluRs), but not NMDA receptors were required for BDNF-produced enhancement. Moreover, calcium-stimulated adenylyl cyclase subtype 1 (AC1) but not AC8 was essential for the enhancement. A selective AC1 inhibitor NB001 completely blocked the enhancement. Furthermore, BDNF-produced enhancement occluded theta burst stimulation (TBS) induced long-term potentiation (LTP), suggesting that they may share similar signaling mechanisms. Finally, the expression of BDNF-induced enhancement depends on postsynaptic incorporation of calcium-permeable AMPA receptors (CP-AMPARs) and protein kinase Mζ (PKMζ). Our results demonstrate that cortical BDNF may contribute to synaptic potentiation in the ACC.
Collapse
Affiliation(s)
- Hui-Hui Miao
- Department of Anesthesiology, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People's Republic of China.,Department of Physiology, Faculty of Medicine, University of Toronto, Medical Science Building, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.,Institute for Brain Research, QingDao International Academician Park, Qing Dao, Shandong, People's Republic of China
| | - Zhuang Miao
- Department of Physiology, Faculty of Medicine, University of Toronto, Medical Science Building, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Ji-Gang Pan
- Department of Physiology, Faculty of Medicine, University of Toronto, Medical Science Building, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Xu-Hui Li
- Department of Physiology, Faculty of Medicine, University of Toronto, Medical Science Building, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada. .,Center for Neuron and Disease, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, Shaanxi, People's Republic of China. .,Institute for Brain Research, QingDao International Academician Park, Qing Dao, Shandong, People's Republic of China.
| | - Min Zhuo
- Department of Physiology, Faculty of Medicine, University of Toronto, Medical Science Building, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada. .,Center for Neuron and Disease, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, Shaanxi, People's Republic of China. .,Institute for Brain Research, QingDao International Academician Park, Qing Dao, Shandong, People's Republic of China.
| |
Collapse
|
|
39
|
Chen QY, Li XH, Zhuo M. NMDA receptors and synaptic plasticity in the anterior cingulate cortex. Neuropharmacology 2021; 197:108749. [PMID: 34364898 DOI: 10.1016/j.neuropharm.2021.108749] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 08/01/2021] [Accepted: 08/03/2021] [Indexed: 10/20/2022]
Abstract
The anterior cingulate cortex (ACC) plays an important role in pain modulation, and pain-related emotional disorders. In the ACC, two major forms of long-term potentiation (LTP) coexist in excitatory synapses and lay the basis of chronic pain and pain-related emotional disorders. The induction of postsynaptic LTP is dependent on the activation of postsynaptic NMDA receptors (NMDARs), while the presynaptic LTP is NMDAR-independent. Long-term depression (LTD) can also be divided into two types according to the degree of sensitivity to the inhibition of NMDARs. NMDAR heteromers containing GluN2A and GluN2B act as key molecules in both the NMDAR-dependent postsynaptic LTP and LTD. Additionally, NMDARs also exist in presynaptic terminals and modulate the evoked and spontaneous transmitter release. From a translational point of view, inhibiting subtypes of NMDARs and/or downstream signaling proteins may provide potential drug targets for chronic pain and its related emotional disorders.
Collapse
Affiliation(s)
- Qi-Yu Chen
- International Institute for Brain Research, Qingdao International Academician Park, Qingdao, China; Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Xu-Hui Li
- International Institute for Brain Research, Qingdao International Academician Park, Qingdao, China; Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Min Zhuo
- International Institute for Brain Research, Qingdao International Academician Park, Qingdao, China; Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, China; Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada.
| |
Collapse
|
|
40
|
Li ZZ, Han WJ, Sun ZC, Chen Y, Sun JY, Cai GH, Liu WN, Wang TZ, Xie YD, Mao HH, Wang F, Ma SB, Wang FD, Xie RG, Wu SX, Luo C. Extracellular matrix protein laminin β1 regulates pain sensitivity and anxiodepression-like behaviors in mice. J Clin Invest 2021; 131:e146323. [PMID: 34156983 DOI: 10.1172/jci146323] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 06/16/2021] [Indexed: 01/11/2023] Open
Abstract
Patients with neuropathic pain often experience comorbid psychiatric disorders. Cellular plasticity in the anterior cingulate cortex (ACC) is assumed to be a critical interface for pain perception and emotion. However, substantial efforts have thus far been focused on the intracellular mechanisms of plasticity rather than the extracellular alterations that might trigger and facilitate intracellular changes. Laminin, a key element of the extracellular matrix (ECM), consists of one α-, one β-, and one γ-chain and is implicated in several pathophysiological processes. Here, we showed in mice that laminin β1 (LAMB1) in the ACC was significantly downregulated upon peripheral neuropathy. Knockdown of LAMB1 in the ACC exacerbated pain sensitivity and induced anxiety and depression. Mechanistic analysis revealed that loss of LAMB1 caused actin dysregulation via interaction with integrin β1 and the subsequent Src-dependent RhoA/LIMK/cofilin pathway, leading to increased presynaptic transmitter release probability and abnormal postsynaptic spine remodeling, which in turn orchestrated the structural and functional plasticity of pyramidal neurons and eventually resulted in pain hypersensitivity and anxiodepression. This study sheds new light on the functional capability of ECM LAMB1 in modulating pain plasticity and identifies a mechanism that conveys extracellular alterations to intracellular plasticity. Moreover, we identified cingulate LAMB1/integrin β1 signaling as a promising therapeutic target for the treatment of neuropathic pain and associated anxiodepression.
Collapse
Affiliation(s)
- Zhen-Zhen Li
- Department of Neurobiology, School of Basic Medicine.,Department of Neurosurgery, Xijing Hospital, and
| | - Wen-Juan Han
- Department of Neurobiology, School of Basic Medicine
| | - Zhi-Chuan Sun
- Department of Neurobiology, School of Basic Medicine
| | - Yun Chen
- The Second Regiment, School of Basic Medicine, Fourth Military Medical University, Xi'an, China
| | - Jun-Yi Sun
- The Second Regiment, School of Basic Medicine, Fourth Military Medical University, Xi'an, China
| | - Guo-Hong Cai
- Department of Neurobiology, School of Basic Medicine
| | - Wan-Neng Liu
- Department of Neurobiology, School of Basic Medicine.,College of Life Sciences, Northwest University, Xi'an, China
| | - Tao-Zhi Wang
- Department of Neurobiology, School of Basic Medicine.,Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, China
| | - Yang-Dan Xie
- The Second Regiment, School of Basic Medicine, Fourth Military Medical University, Xi'an, China
| | - Hong-Hui Mao
- Department of Neurobiology, School of Basic Medicine
| | - Fei Wang
- Department of Neurobiology, School of Basic Medicine.,Medical Experiment Center, Shaanxi University of Chinese Medicine, China
| | - Sui-Bin Ma
- Department of Neurobiology, School of Basic Medicine
| | - Fu-Dong Wang
- Department of Neurobiology, School of Basic Medicine
| | - Rou-Gang Xie
- Department of Neurobiology, School of Basic Medicine
| | - Sheng-Xi Wu
- Department of Neurobiology, School of Basic Medicine
| | - Ceng Luo
- Department of Neurobiology, School of Basic Medicine
| |
Collapse
|
|
41
|
Tan LL, Kuner R. Neocortical circuits in pain and pain relief. Nat Rev Neurosci 2021; 22:458-471. [PMID: 34127843 DOI: 10.1038/s41583-021-00468-2] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/19/2021] [Indexed: 02/07/2023]
Abstract
The sensory, associative and limbic neocortical structures play a critical role in shaping incoming noxious inputs to generate variable pain perceptions. Technological advances in tracing circuitry and interrogation of pathways and complex behaviours are now yielding critical knowledge of neocortical circuits, cellular contributions and causal relationships between pain perception and its abnormalities in chronic pain. Emerging insights into neocortical pain processing suggest the existence of neocortical causality and specificity for pain at the level of subdomains, circuits and cellular entities and the activity patterns they encode. These mechanisms provide opportunities for therapeutic intervention for improved pain management.
Collapse
Affiliation(s)
- Linette Liqi Tan
- Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
| | - Rohini Kuner
- Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
| |
Collapse
|
|
42
|
Yu W, Wu X, Chen Y, Liang Z, Jiang J, Misrani A, Su Y, Peng Y, Chen J, Tang B, Sun M, Long C, Shen J, Yang L. Pelvic Pain Alters Functional Connectivity Between Anterior Cingulate Cortex and Hippocampus in Both Humans and a Rat Model. Front Syst Neurosci 2021; 15:642349. [PMID: 34149369 PMCID: PMC8210850 DOI: 10.3389/fnsys.2021.642349] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 04/26/2021] [Indexed: 01/06/2023] Open
Abstract
The anterior cingulate cortex (ACC) and hippocampus (HIPP) are two key brain regions associated with pain and pain-related affective processing. However, whether and how pelvic pain alters the neural activity and connectivity of the ACC and HIPP under baseline and during social pain, and the underlying cellular and molecular mechanisms, remain unclear. Using functional magnetic resonance imaging (fMRI) combined with electrophysiology and biochemistry, we show that pelvic pain, particularly, primary dysmenorrhea (PDM), causes an increase in the functional connectivity between ACC and HIPP in resting-state fMRI, and a smaller reduction in connectivity during social exclusion in PDM females with periovulatory phase. Similarly, model rats demonstrate significantly increased ACC-HIPP synchronization in the gamma band, associating with reduced modulation by ACC-theta on HIPP-gamma and increased levels of receptor proteins and excitation. This study brings together human fMRI and animal research and enables improved therapeutic strategies for ameliorating pain and pain-related affective processing.
Collapse
Affiliation(s)
- Wenjun Yu
- Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, China
- Department of Radiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- College of Education, Jinggangshan University, Ji’an, China
| | - Xiaoyan Wu
- Department of Radiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- School of Psychology, South China Normal University, Guangzhou, China
| | - Yunan Chen
- School of Life Sciences, South China Normal University, Guangzhou, China
| | - Zhiying Liang
- Department of Radiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jinxiang Jiang
- Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, China
| | - Afzal Misrani
- Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, China
| | - Yun Su
- Department of Radiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yigang Peng
- School of Life Sciences, South China Normal University, Guangzhou, China
| | - Jian Chen
- School of Life Sciences, South China Normal University, Guangzhou, China
| | - Binliang Tang
- School of Life Sciences, South China Normal University, Guangzhou, China
| | - Mengyao Sun
- School of Life Sciences, South China Normal University, Guangzhou, China
| | - Cheng Long
- School of Life Sciences, South China Normal University, Guangzhou, China
| | - Jun Shen
- Department of Radiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Li Yang
- Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, China
| |
Collapse
|
|
43
|
Zhou Z, Shi W, Fan K, Xue M, Zhou S, Chen QY, Lu JS, Li XH, Zhuo M. Inhibition of calcium-stimulated adenylyl cyclase subtype 1 (AC1) for the treatment of neuropathic and inflammatory pain in adult female mice. Mol Pain 2021; 17:17448069211021698. [PMID: 34082635 PMCID: PMC8182195 DOI: 10.1177/17448069211021698] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Cortical long-term potentiation (LTP) serves as a cellular model for chronic
pain. As an important subtype of adenylyl cyclases (ACs), adenylyl cyclase
subtype 1 (AC1) is critical for the induction of cortical LTP in the anterior
cingulate cortex (ACC). Genetic deletion of AC1 or pharmacological inhibition of
AC1 blocked behavioral allodynia in animal models of neuropathic and
inflammatory pain. Our previous experiments have identified a lead candidate AC1
inhibitor, NB001, which is highly selective for AC1 over other AC isoforms, and
found that NB001 is effective in inhibiting behavioral allodynia in animal
models of chronic neuropathic and inflammatory pain. However, previous
experiments were carried out in adult male animals. Considering the potential
gender difference as an important issue in researches of pain and analgesia, we
investigated the effect of NB001 in female chronic pain animal models. We found
that NB001, when administered orally, has an analgesic effect in female animal
models of neuropathic and inflammatory pain without any observable side effect.
Genetic deletion of AC1 also reduced allodynia responses in models of
neuropathic pain and chronic inflammation pain in adult female mice. In brain
slices of adult female mice, bath application of NB001(20 μM) blocked the
induction of LTP in ACC. Our results indicate that calcium-stimulated AC1 is
required for injury-related cortical LTP and behavioral allodynia in both sexes
of adult animals, and NB001 can be used as a potential therapeutic drug for
treating neuropathic and inflammatory pain in man and woman.
Collapse
Affiliation(s)
- Zhaoxiang Zhou
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Wantong Shi
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Kexin Fan
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Man Xue
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Sibo Zhou
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Qi-Yu Chen
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, China.,Institute of Brain Research, Qingdao International Academician Park, Qingdao, Shandong, China
| | - Jing-Shan Lu
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, China.,Institute of Brain Research, Qingdao International Academician Park, Qingdao, Shandong, China
| | - Xu-Hui Li
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, China.,Institute of Brain Research, Qingdao International Academician Park, Qingdao, Shandong, China
| | - Min Zhuo
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, China.,Institute of Brain Research, Qingdao International Academician Park, Qingdao, Shandong, China.,Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
44
|
Correia Rocha IR, Chacur M. Modulatory effects of photobiomodulation in the anterior cingulate cortex of diabetic rats. Photochem Photobiol Sci 2021; 20:781-790. [PMID: 34053000 DOI: 10.1007/s43630-021-00059-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 05/25/2021] [Indexed: 10/21/2022]
Abstract
Anterior Cingulate Cortex (ACC) has a crucial contribution to higher order pain processing. Photobiomodulation (PBM) has being used as integrative medicine for pain treatment and for a variety of nervous system disorders. This study evaluated the effects of PBM in the ACC of diabetic rats. Type 1 diabetes was induced by a single dose of streptozotocin (85 mg/Kg). A total of ten sessions of PBM (pulsed gallium-arsenide laser, 904 nm, 9500 Hz, 6.23 J/cm2) was applied to the rat peripheral nervous system. Glial fibrillary acidic protein (GFAP), mu-opioid receptor (MOR), glutamate receptor 1 (GluR1), and glutamic acid decarboxylase (GAD65/67) protein level expression were analyzed in the ACC of diabetic rats treated with PBM. Our data revealed that PBM decreased 79.5% of GFAP protein levels in the ACC of STZ rats. Moreover, STZ + PBM rats had protein levels of MOR increased 14.7% in the ACC. Interestingly, STZ + PBM rats had a decrease in 70.7% of GluR1 protein level in the ACC. Additionally, PBM decreased 45.5% of GAD65/67 protein levels in the ACC of STZ rats.
Collapse
Affiliation(s)
- Igor Rafael Correia Rocha
- Departamento de Anatomia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Avenue Lineu Prestes 2415, room 007, São Paulo, 05508-900, Brazil
| | - Marucia Chacur
- Departamento de Anatomia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Avenue Lineu Prestes 2415, room 007, São Paulo, 05508-900, Brazil.
| |
Collapse
|
|
45
|
Nociceptor-localized cGMP-dependent protein kinase I is a critical generator for central sensitization and neuropathic pain. Pain 2021; 162:135-151. [PMID: 32773598 DOI: 10.1097/j.pain.0000000000002013] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Patients with neuropathic pain often experience exaggerated pain and anxiety. Central sensitization has been linked with the maintenance of neuropathic pain and may become an autonomous pain generator. Conversely, emerging evidence accumulated that central sensitization is initiated and maintained by ongoing nociceptive primary afferent inputs. However, it remains elusive what mechanisms underlie this phenomenon and which peripheral candidate contributes to central sensitization that accounts for pain hypersensitivity and pain-related anxiety. Previous studies have implicated peripherally localized cGMP-dependent protein kinase I (PKG-I) in plasticity of nociceptors and spinal synaptic transmission as well as inflammatory hyperalgesia. However, whether peripheral PKG-I contributes to cortical plasticity and hence maintains nerve injury-induced pain hypersensitivity and anxiety is unknown. Here, we demonstrated significant upregulation of PKG-I in ipsilateral L3 dorsal root ganglia (DRG), no change in L4 DRG, and downregulation in L5 DRG upon spared nerve injury. Genetic ablation of PKG-I specifically in nociceptors or post-treatment with intervertebral foramen injection of PKG-I antagonist, KT5823, attenuated the development and maintenance of spared nerve injury-induced bilateral pain hypersensitivity and anxiety. Mechanistic analysis revealed that activation of PKG-I in nociceptors is responsible for synaptic potentiation in the anterior cingulate cortex upon peripheral neuropathy through presynaptic mechanisms involving brain-derived neurotropic factor signaling. Our results revealed that PKG-I expressed in nociceptors is a key determinant for cingulate synaptic plasticity after nerve injury, which contributes to the maintenance of pain hypersensitivity and anxiety. Thereby, this study presents a strong basis for opening up a novel therapeutic target, PKG-I, in nociceptors for treatment of comorbidity of neuropathic pain and anxiety with least side effects.
Collapse
|
|
46
|
Ofoghi Z, Rohr CS, Dewey D, Bray S, Yeates KO, Noel M, Barlow KM. Functional connectivity of the anterior cingulate cortex with pain-related regions in children with post-traumatic headache. CEPHALALGIA REPORTS 2021. [DOI: 10.1177/25158163211009477] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Introduction: Post-traumatic headaches (PTH) are common following mild traumatic brain injury (mTBI). There is evidence of altered central pain processing in adult PTH; however, little is known about how children with PTH process pain. The anterior cingulate cortex (ACC) plays a critical role in descending central pain modulation. In this study, we explored whether the functional connectivity (FC) of the ACC is altered in children with PTH. Methods: In this case-control study, we investigated resting-state FC of 5 ACC seeds (caudal, dorsal, rostral, perigenual, and subgenual) in children with PTH ( n = 73) and without PTH ( n = 29) following mTBI, and healthy controls ( n = 27). Post-concussion symptoms were assessed using the Post-Concussion Symptom Inventory and the Child Health Questionnaire. Resting-state functional Magnetic Resonance Imaging (fMRI) data were used to generate maps of ACC FC. Group-level comparisons were performed within a target mask comprised of pain-related regions using FSL Randomise. Results: We found decreased FC between the right perigenual ACC and the left cerebellum, and increased FC between the right subgenual ACC and the left dorsolateral prefrontal cortex in children with PTH compared to healthy controls. The ACC FC in children without PTH following mTBI did not differ from the group with PTH or healthy controls. FC between rostral and perigenual ACC seeds and the cerebellum was increased in children with PTH with pre-injury headaches compared to those with PTH without pre-injury headaches. There was a positive relationship between PTH severity and rostral ACC FC with the bilateral thalamus, right hippocampus and periaqueductal gray. Conclusions: Central pain processing is altered in children with PTH. Pre-existing headaches help to drive this process. Trial registration: The PlayGame Trial was registered in ClinicalTrials.gov database ( ClinicalTrials.gov Identifier: NCT01874847).
Collapse
Affiliation(s)
- Zahra Ofoghi
- Department of Neuroscience, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Christiane S Rohr
- Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Child and Adolescent Imaging Research Program, University of Calgary, Calgary, Alberta, Canada
| | - Deborah Dewey
- Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Paediatrics, Cumming School of Medicine University of Calgary, Calgary, Alberta, Canada
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Owerko Centre at the Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Signe Bray
- Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Child and Adolescent Imaging Research Program, University of Calgary, Calgary, Alberta, Canada
| | - Keith Owen Yeates
- Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Psychology, University of Calgary, Calgary, Alberta, Canada
| | - Melanie Noel
- Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Psychology, University of Calgary, Calgary, Alberta, Canada
| | - Karen M Barlow
- Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
- Department of Paediatrics, Cumming School of Medicine University of Calgary, Calgary, Alberta, Canada
- Paediatric Neurology Child Health Research Centre, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| |
Collapse
|
|
47
|
Zhang F, Li F, Yang H, Jin Y, Lai W, Roberts N, Jia Z, Gong Q. Effect of experimental orthodontic pain on gray and white matter functional connectivity. CNS Neurosci Ther 2021; 27:439-448. [PMID: 33369178 PMCID: PMC7941220 DOI: 10.1111/cns.13557] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 11/09/2020] [Accepted: 11/27/2020] [Indexed: 02/05/2023] Open
Abstract
AIM Over 90% of patients receiving orthodontic treatment experience clinically significant pain. However, little is known about the neural correlates of orthodontic pain and which has therefore been investigated in the present study of healthy subjects using an experimental paradigm. METHODS Resting-state functional magnetic resonance imaging (rsfMRI) was performed in 44 healthy subjects 24 hours after an elastic separator had been introduced between the first and the second molar on the right side of the lower jaw and in 49 age- and sex-matched healthy control (HC) subjects. A K-means clustering algorithm was used to identify functional gray matter (GM) and white matter (WM) resting-state networks, and differences in functional connectivity (FC) of GM and WM between the group of subjects with experimental orthodontic pain and HC were analyzed. RESULTS Twelve GM networks and 14 WM networks with high stability were identified. Compared with HC, subjects with orthodontic pain showed significantly increased FC between WM12, which includes posterior thalamic radiation and posterior cingulum bundle, and most GM networks. Besides, the WM12 network showed significant differences in FC with three GM-WM loops involving the default mode network, dorsal attention network, and salience network, respectively. CONCLUSIONS Orthodontic pain is shown to produce an alteration of FC in networks relevant to pain processing, which may be mediated by a WM network relevant to emotion perception and cognitive processing.
Collapse
Affiliation(s)
- Feifei Zhang
- Huaxi MR Research Center (HMRRC)Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan UniversityChengduChina
- Research Unit of PsychoradiologyChinese Academy of Medical SciencesChengduChina
| | - Fei Li
- Huaxi MR Research Center (HMRRC)Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan UniversityChengduChina
- Research Unit of PsychoradiologyChinese Academy of Medical SciencesChengduChina
| | - Hong Yang
- State Key Laboratory of Oral DiseaseDepartment of OrthodonticsWest China School of Stomatology, Sichuan UniversityChengdu
| | - Yu Jin
- State Key Laboratory of Oral DiseaseDepartment of OrthodonticsWest China School of Stomatology, Sichuan UniversityChengdu
| | - Wenli Lai
- State Key Laboratory of Oral DiseaseDepartment of OrthodonticsWest China School of Stomatology, Sichuan UniversityChengdu
| | - Neil Roberts
- School of Clinical SciencesUniversity of EdinburghEdinburghUK
| | - Zhiyun Jia
- Huaxi MR Research Center (HMRRC)Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan UniversityChengduChina
- Department of Nuclear MedicineWest China Hospital of Sichuan UniversityChengduChina
| | - Qiyong Gong
- Huaxi MR Research Center (HMRRC)Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan UniversityChengduChina
- Research Unit of PsychoradiologyChinese Academy of Medical SciencesChengduChina
| |
Collapse
|
|
48
|
Liu TH, Wang Z, Xie F, Liu YQ, Lin Q. Contributions of aversive environmental stress to migraine chronification: Research update of migraine pathophysiology. World J Clin Cases 2021; 9:2136-2145. [PMID: 33850932 PMCID: PMC8017499 DOI: 10.12998/wjcc.v9.i9.2136] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 02/03/2021] [Accepted: 03/16/2021] [Indexed: 02/06/2023] Open
Abstract
Clinical studies have suggested that internal and/or external aversive cues may produce a negative affective-motivational component whereby maladaptive responses (plasticity) of dural afferent neurons are initiated contributing to migraine chronification. However, pathophysiological processes and neural circuitry involved in aversion (unpleasantness)-producing migraine chronification are still evolving. An interdisciplinary team conducted this narrative review aimed at reviewing neuronal plasticity for developing migraine chronicity and its relevant neurocircuits and providing the most cutting-edge information on neuronal mechanisms involved in the processing of affective aspects of pain and the role of unpleasantness evoked by internal and/or external cues in facilitating the chronification process of migraine headache. Thus, information presented in this review promotes the understanding of the pathophysiology of chronic migraine and contribution of unpleasantness (aversion) to migraine chronification. We hope that it will bring clinicians’ attention to how the maladaptive neuroplasticity of the emotion brain in the aversive environment produces a significant impact on the chronification of migraine headache, which will in turn lead to new therapeutic strategies for this type of pain.
Collapse
Affiliation(s)
- Tang-Hua Liu
- Department of Algology, The Third People's Hospital of Yibin, Yibin 644000, Sichuan Province, China
| | - Zhen Wang
- Department of Psychology, University of Texas at Arlington, Arlington, TX 76019, United States
| | - Fang Xie
- Department of Algology, The Third People's Hospital of Yibin, Yibin 644000, Sichuan Province, China
| | - Yan-Qing Liu
- Department of Algology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Qing Lin
- Department of Psychology, University of Texas at Arlington, Arlington, TX 76019, United States
| |
Collapse
|
|
49
|
Chen QY, Li XH, Lu JS, Liu Y, Lee JHA, Chen YX, Shi W, Fan K, Zhuo M. NMDA GluN2C/2D receptors contribute to synaptic regulation and plasticity in the anterior cingulate cortex of adult mice. Mol Brain 2021; 14:60. [PMID: 33766086 PMCID: PMC7995764 DOI: 10.1186/s13041-021-00744-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 02/02/2021] [Indexed: 01/25/2023] Open
Abstract
INTRODUCTION N-Methyl-D-aspartate receptors (NMDARs) play a critical role in different forms of plasticity in the central nervous system. NMDARs are always assembled in tetrameric form, in which two GluN1 subunits and two GluN2 and/or GluN3 subunits combine together. Previous studies focused mainly on the hippocampus. The anterior cingulate cortex (ACC) is a key cortical region for sensory and emotional functions. NMDAR GluN2A and GluN2B subunits have been previously investigated, however much less is known about the GluN2C/2D subunits. RESULTS In the present study, we found that the GluN2C/2D subunits are expressed in the pyramidal cells of ACC of adult mice. Application of a selective antagonist of GluN2C/2D, (2R*,3S*)-1-(9-bromophenanthrene-3-carbonyl) piperazine-2,3-dicarboxylic acid (UBP145), significantly reduced NMDAR-mediated currents, while synaptically evoked EPSCs were not affected. UBP145 affected neither the postsynaptic long-term potentiation (post-LTP) nor the presynaptic LTP (pre-LTP). Furthermore, the long-term depression (LTD) was also not affected by UBP145. Finally, both UBP145 decreased the frequency of the miniature EPSCs (mEPSCs) while the amplitude remained intact, suggesting that the GluN2C/2D may be involved in presynaptic regulation of spontaneous glutamate release. CONCLUSIONS Our results provide direct evidence that the GluN2C/2D contributes to evoked NMDAR mediated currents and mEPSCs in the ACC, which may have significant physiological implications.
Collapse
Affiliation(s)
- Qi-Yu Chen
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, China.,International Institute for Brain Research, Qingdao International Academician Park, Qingdao, China
| | - Xu-Hui Li
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, China.,International Institute for Brain Research, Qingdao International Academician Park, Qingdao, China.,Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, ON, Canada
| | - Jing-Shan Lu
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, China.,International Institute for Brain Research, Qingdao International Academician Park, Qingdao, China
| | - Yinglu Liu
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, China.,Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, ON, Canada
| | - Jung-Hyun Alex Lee
- Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, ON, Canada
| | - Yu-Xin Chen
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Wantong Shi
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Kexin Fan
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Min Zhuo
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, China. .,International Institute for Brain Research, Qingdao International Academician Park, Qingdao, China. .,Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, ON, Canada.
| |
Collapse
|
|
50
|
Alonso-Matielo H, Gonçalves ES, Campos M, Oliveira VRS, Toniolo EF, Alves AS, Lebrun I, de Andrade DC, Teixeira MJ, Britto LRG, Hamani C, Dale CS. Electrical stimulation of the posterior insula induces mechanical analgesia in a rodent model of neuropathic pain by modulating GABAergic signaling and activity in the pain circuitry. Brain Res 2021; 1754:147237. [PMID: 33400930 DOI: 10.1016/j.brainres.2020.147237] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 11/09/2020] [Accepted: 12/07/2020] [Indexed: 12/19/2022]
Abstract
The insula has emerged as a critical target for electrical stimulation since it influences pathological pain states. We investigated the effects of repetitive electrical stimulation of the insular cortex (ESI) on mechanical nociception, and general locomotor activity in rats subjected to chronic constriction injury (CCI) of the sciatic nerve. We also studied neuroplastic changes in central pain areas and the involvement of GABAergic signaling on ESI effects. CCI rats had electrodes implanted in the left agranular posterior insular cortex (pIC), and mechanical sensitivity was evaluated before and after one or five daily consecutive ESIs (15 min each, 60 Hz, 210 μs, 1 V). Five ESIs (repetitive ESI) induced sustained mechanical antinociception from the first to the last behavioral assessment without interfering with locomotor activity. A marked increase in Fos immunoreactivity in pIC and a decrease in the anterior and mid-cingulate cortex, periaqueductal gray and hippocampus were noticed after five ESIs. The intrathecal administration of the GABAA receptor antagonist bicuculline methiodide reversed the stimulation-induced antinociception after five ESIs. ESI increased GAD65 levels in pIC but did not interfere with GABA, glutamate or glycine levels. No changes in GFAP immunoreactivity were found in this work. Altogether, the results indicate the efficacy of repetitive ESI for the treatment of experimental neuropathic pain and suggest a potential influence of pIC in regulating pain pathways partially through modulating GABAergic signaling.
Collapse
Affiliation(s)
- Heloísa Alonso-Matielo
- Department of Anatomy, Institute of Biomedical Sciences of University of São Paulo - Av. Prof. Lineu Prestes, 2415, ICB-III, Cidade Universitária, 05508-900 São Paulo, SP, Brazil
| | - Elizamara S Gonçalves
- Department of Anatomy, Institute of Biomedical Sciences of University of São Paulo - Av. Prof. Lineu Prestes, 2415, ICB-III, Cidade Universitária, 05508-900 São Paulo, SP, Brazil
| | - Mariana Campos
- Department of Anatomy, Institute of Biomedical Sciences of University of São Paulo - Av. Prof. Lineu Prestes, 2415, ICB-III, Cidade Universitária, 05508-900 São Paulo, SP, Brazil
| | - Victória R S Oliveira
- Department of Anatomy, Institute of Biomedical Sciences of University of São Paulo - Av. Prof. Lineu Prestes, 2415, ICB-III, Cidade Universitária, 05508-900 São Paulo, SP, Brazil
| | - Elaine F Toniolo
- Center of Research in Neuroscience, Universidade Cidade de São Paulo, R. Cesário Galero, 448/475 - Tatuapé, São Paulo, SP 03071-000, Brazil
| | - Adilson S Alves
- Department of Physiology and Biophysics, Institute of Biomedical Sciences of University of São Paulo - Av. Prof. Lineu Prestes, 1524, ICB-I, Cidade Universitária, 05508-000 São Paulo, SP, Brazil
| | - Ivo Lebrun
- Laboratoryof Biochemistry and Biophysics, Institute Butantan, São Paulo, Brazil
| | - Daniel C de Andrade
- Department of Neurology, Central Institute, Av. Dr Enéas de Carvalho Aguiar, 255, 5(th) Floor, Room 5084, Cerqueira César, 05403-900 São Paulo, SP, Brazil; Instituto do Câncer Octavio Frias de Oliveira, University of São Paulo, Brazil
| | - Manoel J Teixeira
- Department of Neurology, Central Institute, Av. Dr Enéas de Carvalho Aguiar, 255, 5(th) Floor, Room 5084, Cerqueira César, 05403-900 São Paulo, SP, Brazil
| | - Luiz R G Britto
- Department of Physiology and Biophysics, Institute of Biomedical Sciences of University of São Paulo - Av. Prof. Lineu Prestes, 1524, ICB-I, Cidade Universitária, 05508-000 São Paulo, SP, Brazil
| | - Clement Hamani
- Harquail Centre for Neuromodulation, Sunnybrook Research Institute, University of Toronto, Toronto, ON M4N3M5, Canada
| | - Camila S Dale
- Department of Anatomy, Institute of Biomedical Sciences of University of São Paulo - Av. Prof. Lineu Prestes, 2415, ICB-III, Cidade Universitária, 05508-900 São Paulo, SP, Brazil; Department of Surgical Technique, Medical School, University of São Paulo, Av. Dr. Arnaldo, 455, 01246-903 São Paulo, SP, Brazil.
| |
Collapse
|