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Hasegawa R, Nakaya K, Kanazawa M, Fukudo S. Corticotropin-releasing hormone receptor-1 antagonist attenuates visceral hypersensitivity induced by trinitrobenzene sulfonic acid colitis and maternal separation in rats. Biopsychosoc Med 2025; 19:5. [PMID: 40155981 PMCID: PMC11951537 DOI: 10.1186/s13030-025-00324-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 01/21/2025] [Indexed: 04/01/2025] Open
Abstract
BACKGROUND The prevailing paradigm for the etiology of irritable bowel syndrome is that transient noxious events lead to long-lasting sensitization of the neural pain circuit, despite complete resolution of the initiating event. In this study, we tested the hypotheses that (1) the combination of maternal separation (MS) and previous colorectal inflammation induces extensive visceral hypersensitivity in rats and (2) visceral hypersensitivity induced by maternal separation and previous colorectal inflammation in rats is mediated via the corticotropin-releasing hormone receptor-1 (CRH-R1) pathway. METHODS Male rat pups were separated from their dams from postnatal day 2 to postnatal day 21. Acute colitis was induced by colorectal administration of trinitrobenzene sulfonic acid (TNBS) or vehicle on postnatal day 8. On postnatal day 50, the visceromotor response was evaluated by electromyography of the abdominal muscle in response to graded (10-80 mmHg) and phasic colorectal distention (CRD) one time. The same experiments were repeated after administration of the selective CRH-R1 antagonist CP-154,526 (20 mg/kg) or vehicle at 45 min before CRD. RESULTS Compared with control rats, visceral perception was increased in MS + TNBS rats. MS + TNBS rats showed a significantly larger visceromotor response to phasic CRD with 40 mmHg, 60 mmHg, and 80 mmHg. Compared with vehicle administration in MS + TNBS rats, administration of CP-154,526 significantly attenuated this visceromotor response to CRD with 40 mmHg, 60 mmHg, and 80 mmHg. CONCLUSIONS These findings suggest that the combination of previous colitis and early life stress induce visceral hypersensitivity, and that the CRH-R1 pathway may play a role in this sensitization.
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Affiliation(s)
- Ryoko Hasegawa
- Department of Behavioral Medicine, Tohoku University Graduate School of Medicine, 2-1 Seiryo, Aoba, Sendai, 980-8575, Japan
| | - Kumi Nakaya
- Department of Behavioral Medicine, Tohoku University Graduate School of Medicine, 2-1 Seiryo, Aoba, Sendai, 980-8575, Japan
- Division of Epidemiology, School of Public Health, Tohoku University Graduate School of Medicine, Sendai, Japan
- Division of Personalized Prevention and Epidemiology Department of Preventive Medicine and Epidemiology Tohoku Medical Megabank Organization, Sendai, Japan
| | - Motoyori Kanazawa
- Department of Behavioral Medicine, Tohoku University Graduate School of Medicine, 2-1 Seiryo, Aoba, Sendai, 980-8575, Japan
- Department of Psychosomatic Medicine, Tohoku University Hospital, Sendai, Japan
| | - Shin Fukudo
- Department of Behavioral Medicine, Tohoku University Graduate School of Medicine, 2-1 Seiryo, Aoba, Sendai, 980-8575, Japan.
- Department of Psychosomatic Medicine, Tohoku University Hospital, Sendai, Japan.
- Research Center for Accelerator and Radioisotope Science, Tohoku University, Sendai, Japan.
- Department of Psychosomatic Medicine, Japanese Red Cross Ishinomaki Hospital, Ishinomaki, Japan.
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Harbour K, Baccei ML. Influence of Early-Life Stress on the Excitability of Dynorphin Neurons in the Adult Mouse Dorsal Horn. THE JOURNAL OF PAIN 2024; 25:104609. [PMID: 38885917 PMCID: PMC11815514 DOI: 10.1016/j.jpain.2024.104609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 05/24/2024] [Accepted: 06/11/2024] [Indexed: 06/20/2024]
Abstract
While early-life adversity has been associated with a higher risk of developing chronic pain in adulthood, the cellular and molecular mechanisms by which chronic stress during the neonatal period can persistently sensitize developing nociceptive circuits remain poorly understood. Here, we investigate the effects of early-life stress (ELS) on synaptic integration and intrinsic excitability in dynorphin-lineage (DYN) interneurons within the adult mouse superficial dorsal horn (SDH), which are important for inhibiting mechanical pain and itch. The administration of neonatal limited bedding between postnatal days (P)2 and P9 evoked sex-dependent effects on spontaneous glutamatergic signaling, as female SDH neurons exhibited a higher amplitude of miniature excitatory postsynaptic currents (mEPSCs) after ELS, while mEPSC frequency was reduced in DYN neurons of the male SDH. Furthermore, ELS decreased the frequency of miniature inhibitory postsynaptic currents selectively in female DYN neurons. As a result, ELS increased the balance of spontaneous excitation versus inhibition (E:I ratio) in mature DYN neurons of the female, but not male, SDH network. Nonetheless, ELS weakened the total primary afferent-evoked glutamatergic drive onto adult DYN neurons selectively in females, without modifying afferent-evoked inhibitory signaling onto the DYN population. Finally, ELS failed to significantly change the intrinsic membrane excitability of mature DYN neurons in either males or females. Collectively, these data suggest that ELS exerts a long-term influence on the properties of synaptic transmission onto DYN neurons within the adult SDH, which includes a reduction in the overall strength of sensory input onto this important subset of inhibitory interneurons. PERSPECTIVE: This study suggests that chronic stress during the neonatal period influences synaptic function within adult spinal nociceptive circuits in a sex-dependent manner. These findings yield new insight into the potential mechanisms by which early-life adversity might shape the maturation of pain pathways in the central nervous system (CNS).
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Affiliation(s)
- Kyle Harbour
- Molecular, Cellular and Biochemical Pharmacology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Anesthesiology, Pain Research Center, University of Cincinnati Medical Center, Cincinnati, Ohio
| | - Mark L Baccei
- Molecular, Cellular and Biochemical Pharmacology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Anesthesiology, Pain Research Center, University of Cincinnati Medical Center, Cincinnati, Ohio.
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Liu J, Dai Q, Qu T, Ma J, Lv C, Wang H, Yu Y. Ameliorating effects of transcutaneous auricular vagus nerve stimulation on a mouse model of constipation-predominant irritable bowel syndrome. Neurobiol Dis 2024; 193:106440. [PMID: 38369213 DOI: 10.1016/j.nbd.2024.106440] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 02/05/2024] [Accepted: 02/15/2024] [Indexed: 02/20/2024] Open
Abstract
Limited treatment options have been shown to alter the natural course of constipation-predominant irritable bowel syndrome (IBS-C). Therefore, safer and more effective approaches are urgently needed. We investigated the effects of transcutaneous auricular vagus nerve stimulation (taVNS) in a mouse model of IBS-C. In the current study, C57BL/6 mice were randomly divided into normal control, IBS-C model control, sham-electrostimulation (sham-ES), taVNS, and drug treatment groups. The effects of taVNS on fecal pellet number, fecal water content, and gastrointestinal transit were evaluated in IBS-C model mice. We assessed the effect of taVNS on visceral hypersensitivity using the colorectal distention test. 16S rRNA sequencing was used to analyze the fecal microbiota of the experimental groups. First, we found that taVNS increased fecal pellet number, fecal water content, and gastrointestinal transit in IBS-C model mice compared with the sham-ES group. Second, taVNS significantly decreased the abdominal withdrawal reflex (AWR) score compared with the sham-ES group, thus relieving visceral hyperalgesia. Third, the gut microbiota outcomes showed that taVNS restored Lactobacillus abundance while increasing Bifidobacterium probiotic abundance at the genus level. Notably, taVNS increased the number of c-kit-positive interstitial cells of Cajal (ICC) in the myenteric plexus region in IBS-C mice compared with the sham-ES group. Therefore, our study indicated that taVNS effectively ameliorated IBS-C in the gut microbiota and ICC.
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Affiliation(s)
- Jie Liu
- Department of Gastroenterology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
| | - Qian Dai
- College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei 230001, Anhui Province, China
| | - Tong Qu
- College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei 230001, Anhui Province, China
| | - Jun Ma
- Department of Anesthesiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
| | - Chaolan Lv
- Department of Gastroenterology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
| | - Haitao Wang
- College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei 230001, Anhui Province, China.
| | - Yue Yu
- Department of Gastroenterology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China.
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Brosens N, Simon C, Kessels HW, Lucassen PJ, Krugers HJ. Early life stress lastingly alters the function and AMPA-receptor composition of glutamatergic synapses in the hippocampus of male mice. J Neuroendocrinol 2023; 35:e13346. [PMID: 37901923 DOI: 10.1111/jne.13346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 08/15/2023] [Accepted: 08/28/2023] [Indexed: 10/31/2023]
Abstract
Early postnatal life is a sensitive period of development that shapes brain structure and function later in life. Exposure to stress during this critical time window can alter brain development and may enhance the susceptibility to psychopathology and neurodegenerative disorders later in life. The developmental effects of early life stress (ELS) on synaptic function are not fully understood, but could provide mechanistic insights into how ELS modifies later brain function and disease risk. We here assessed the effects of ELS on synaptic function and composition in the hippocampus of male mice. Mice were subjected to ELS by housing dams and pups with limited bedding and nesting material from postnatal days (P) 2-9. Synaptic strength was measured in terms of miniature excitatory postsynaptic currents (mEPSCs) in the hippocampal dentate gyrus at three different developmental stages: the early postnatal phase (P9), preadolescence (P21, at weaning) and adulthood at 3 months of age (3MO). Hippocampal synaptosome fractions were isolated from P9 and 3MO tissue and analyzed for protein content to assess postsynaptic composition. Finally, dendritic spine density was assessed in the DG at 3MO. At P9, ELS increased mEPSC frequency and amplitude. In parallel, synaptic composition was altered as PSD-95, GluA3 and GluN2B content were significantly decreased. The increased mEPSC frequency was sustained up to 3MO, at which age, GluA3 content was significantly increased. No differences were found in dendritic spine density. These findings highlight how ELS affects the development of hippocampal synapses, which could provide valuable insight into mechanisms how ELS alters brain function later in life.
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Affiliation(s)
- Niek Brosens
- SILS-CNS, University of Amsterdam, Amsterdam, The Netherlands
| | - Carla Simon
- SILS-CNS, University of Amsterdam, Amsterdam, The Netherlands
| | | | - Paul J Lucassen
- SILS-CNS, University of Amsterdam, Amsterdam, The Netherlands
| | - Harm J Krugers
- SILS-CNS, University of Amsterdam, Amsterdam, The Netherlands
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5
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Noor-Mohammadi E, Ligon CO, Mackenzie KD, Stratton J, Shnider SJ, Greenwood-Van Meerveld B. Antinociceptive Effects of an Anti-CGRP Antibody in Rat Models of Colon-Bladder Cross-Organ Sensitization. J Pharmacol Exp Ther 2023; 387:4-14. [PMID: 37164371 DOI: 10.1124/jpet.122.001480] [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: 09/30/2022] [Revised: 04/10/2023] [Accepted: 04/22/2023] [Indexed: 05/12/2023] Open
Abstract
Irritable bowel syndrome (IBS) and bladder pain syndrome/interstitial cystitis (BPS/IC) are comorbid visceral pain disorders seen commonly in women with unknown etiology and limited treatment options and can involve visceral organ cross-sensitization. Calcitonin gene-related peptide (CGRP) is a mediator of nociceptive processing and may serve as a target for therapy. In three rodent models, we employed a monoclonal anti-CGRP F(ab')2 to investigate the hypothesis that visceral organ cross-sensitization is mediated by abnormal CGRP signaling. Visceral organ cross-sensitization was induced in adult female rats via transurethral infusion of protamine sulfate (PS) into the urinary bladder or infusion into the colon of trinitrobenzene sulfonic acid (TNBS). Colonic sensitivity was assessed via the visceromotor response to colorectal distension (CRD). Bladder sensitivity was assessed as the frequency of abdominal withdrawal reflexes to von Frey filaments applied to the suprapubic region. PS- or TNBS-induced changes in colonic and bladder permeability were investigated in vitro via quantification of transepithelial electrical resistance (TEER). Peripheral administration of an anti-CGRP F(ab')2 inhibited PS-induced visceral pain behaviors and colon hyperpermeability. Similarly, TNBS-induced pain behaviors and colon and bladder hyperpermeability were attenuated by anti-CGRP F(ab')2 treatment. PS into the bladder or TNBS into the colon significantly increased the visceromotor response to CRD and abdominal withdrawal reflexes to suprapubic stimulation and decreased bladder and colon TEER. These findings suggest an important role of peripheral CGRP in visceral nociception and organ cross-sensitization and support the evaluation of CGRP as a therapeutic target for visceral pain in patients with IBS and/or BPS/IC. SIGNIFICANCE STATEMENT: A monoclonal antibody against calcitonin gene-related peptide (CGRP) was found to reduce concomitant colonic and bladder hypersensitivity and hyperpermeability. The results of this study suggest that CGRP-targeting antibodies, in addition to migraine prevention, may provide a novel treatment strategy for multiorgan abdominopelvic pain following injury or inflammation.
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Affiliation(s)
- Ehsan Noor-Mohammadi
- Department of Physiology (E.N.-M., C.O.L., B.G.-V.M.), University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; and TEVA Pharmaceuticals Ltd. (K.D.M., J.S., S.J.S.), Redwood City, California
| | - Casey O Ligon
- Department of Physiology (E.N.-M., C.O.L., B.G.-V.M.), University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; and TEVA Pharmaceuticals Ltd. (K.D.M., J.S., S.J.S.), Redwood City, California
| | - Kimberly D Mackenzie
- Department of Physiology (E.N.-M., C.O.L., B.G.-V.M.), University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; and TEVA Pharmaceuticals Ltd. (K.D.M., J.S., S.J.S.), Redwood City, California
| | - Jennifer Stratton
- Department of Physiology (E.N.-M., C.O.L., B.G.-V.M.), University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; and TEVA Pharmaceuticals Ltd. (K.D.M., J.S., S.J.S.), Redwood City, California
| | - Sara J Shnider
- Department of Physiology (E.N.-M., C.O.L., B.G.-V.M.), University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; and TEVA Pharmaceuticals Ltd. (K.D.M., J.S., S.J.S.), Redwood City, California
| | - Beverley Greenwood-Van Meerveld
- Department of Physiology (E.N.-M., C.O.L., B.G.-V.M.), University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; and TEVA Pharmaceuticals Ltd. (K.D.M., J.S., S.J.S.), Redwood City, California
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Effect of Riluzole on the Expression of HCN2 in Dorsal Root Ganglion Neurons of Diabetic Neuropathic Pain Rats. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:8313415. [PMID: 35432830 PMCID: PMC9007632 DOI: 10.1155/2022/8313415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 03/09/2022] [Accepted: 03/12/2022] [Indexed: 11/18/2022]
Abstract
Neuropathic pain since early diabetes swamps patients' lives, and diabetes mellitus has become an increasingly worldwide epidemic. No agent, so far, can terminate the ongoing diabetes. Therefore, strategies that delay the process and the further complications are preferred, such as diabetic neuropathic pain (DNP). Dysfunction of ion channels is generally accepted as the central mechanism of diabetic associated neuropathy, of which hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) ion channel has been verified the involvement of neuropathic pain in dorsal root ganglion (DRG) neurons. Riluzole is a benzothiazole compound with neuroprotective properties on intervention to various ion channels, including hyperpolarization-activated voltage-dependent channels. To investigate the effect of riluzole within lumbar (L3-5) DRG neurons from DNP models, streptozocin (STZ, 70 mg/kg) injection was recruited subcutaneously followed by paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL), which both show significant reduction, whilst relieved by riluzole (4 mg/kg/d) administration, which was performed once daily for 7 consecutive days for 14 days. HCN2 expression was also decreased in line with alleviated behavioral tests. Our results indicate riluzole as the alleviator to STZ-induced DNP with involvement of downregulated HCN2 in lumbar DRG by continual systemic administration in rats.
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7
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Tao E, Long G, Yang T, Chen B, Guo R, Ye D, Fang M, Jiang M. Maternal Separation Induced Visceral Hypersensitivity Evaluated via Novel and Small Size Distention Balloon in Post-weaning Mice. Front Neurosci 2022; 15:803957. [PMID: 35153662 PMCID: PMC8831756 DOI: 10.3389/fnins.2021.803957] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/20/2021] [Indexed: 11/29/2022] Open
Abstract
Early life stress (ELS) disposes to functional gastrointestinal diseases in adult, such as irritable bowel syndrome (IBS). Maternal separation (MS) is a well-known animal model of IBS and has been shown to induce visceral hypersensitivity in adult rats and mice. However, to the best of our knowledge, it has not been reported whether MS induces visceral hypersensitivity in young mice, such as the post-weaning mice. Moreover, the method for evaluation of visceral sensitivity also has not been described. Accordingly, the present study aims to evaluate the visceral sensitivity caused by MS in post-weaning mice and develop a novel and small size distention balloon for assessment of visceral sensitivity of such mice. Male pups of C57BL/6 mice were randomly divided into two groups, MS (n = 12) and non-separation (NS) (n = 10). MS pups were separated from the dams through postnatal days (PND) 2 to 14, while NS pups were undisturbed. After, all pups stayed with respective dams and were weaned at PND 22. Visceral sensitivity was evaluated by colorectal distention (CRD) with a novel and small size distention balloon at PND 25. The threshold of abdominal withdrawal reflex (AWR) scores were significantly lower in MS than NS. In addition, AWR scores at different pressures of CRD were significantly higher in MS than NS. The results demonstrate that MS induced visceral hypersensitivity in post-weaning mice. The designed small size distention balloon for evaluation of visceral sensitivity is of significance to further study the pathophysiology of IBS from early life to adulthood.
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Affiliation(s)
- Enfu Tao
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
- Department of Pediatrics, Wenling Maternal and Child Health Care Hospital, Wenling, China
| | - Gao Long
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Ting Yang
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Bo Chen
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Rui Guo
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Diya Ye
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Marong Fang
- Institute of Neuroscience and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Mizu Jiang
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
- *Correspondence: Mizu Jiang,
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8
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Chen T, Chen S, Zheng X, Zhu Y, Huang Z, Jia L, OuYang L, Lei W. The pathological involvement of spinal cord EphB2 in visceral sensitization in male rats. Stress 2022; 25:166-178. [PMID: 35435121 DOI: 10.1080/10253890.2022.2054698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Abstract
Patients with post-traumatic stress disorder (PTSD) are usually at an increased risk for chronic disorders, such as irritable bowel syndrome (IBS), characterized by hyperalgesia and allodynia, but its subsequent effect on visceral hyperalgesia and the mechanism remain unclear. The present study employed single prolonged stress (SPS), a model of PTSD-pain comorbidity, behavioral evaluation, intrathecal drug delivery, immunohistochemistry, Western blotting, and RT-PCR techniques. When detecting visceral sensitivity, the score of the abdominal withdrawal reflex (AWR) induced by graded colorectal distention (CRD) was used. The AWR score was reduced in the SPS day 1 group but increased in the SPS day 7 and SPS day 14 groups at 40 mmHg and 60 mmHg, and the score was increased significantly with EphrinB1-Fc administration. The EphB2+ cell density and EphB2 protein and mRNA levels were downregulated in the SPS day 1 group and then upregulated significantly in the SPS day 7 group; these changes were more noticeable with EphrinB1-Fc administration compared with the SPS-only group. The C-Fos-positive reaction induced by SPS was mainly localized in neurons of the spinal dorsal horn, in which the C-Fos-positive cell density and its protein and mRNA levels were upregulated on SPS days 7 and 14; these changes were statistically significant in the SPS + EphrinB1-Fc group compared with the SPS alone group. The present study confirmed the time window for the AWR value, EphB2 and C-Fos changes, and the effect of EphrinB1-Fc on these changes, which suggests that spinal cord EphB2 activation exacerbates visceral pain after SPS.
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Affiliation(s)
- Tao Chen
- Department of Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Si Chen
- Department of Human Anatomy and Histology & Embryology, Zhuhai Campus of Zunyi Medical University, Zhuhai, China
| | - Xuefeng Zheng
- Neuroscience Laboratory for Cognitive and Developmental Disorders, Department of Anatomy, Medical College of Jinan University, Guangzhou, China
| | - Yaofeng Zhu
- Department of Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Ziyun Huang
- Department of Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Linju Jia
- Department of Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Lisi OuYang
- Department of Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Wanlong Lei
- Department of Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
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Wang Y, Peng Y, Zhang C, Zhou X. Astrocyte-neuron lactate transport in the ACC contributes to the occurrence of long-lasting inflammatory pain in male mice. Neurosci Lett 2021; 764:136205. [PMID: 34478818 DOI: 10.1016/j.neulet.2021.136205] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 08/24/2021] [Accepted: 08/29/2021] [Indexed: 12/20/2022]
Abstract
Lactate transport is an important means of communication between astrocytes and neurons and is implicated in a variety of neurobiological processes. However, the connection between astrocyte-neuron lactate transport and nociceptive modulation has not been well established. Here, we found that Complete Freund's adjuvant (CFA)-induced inflammation pain leads to a significant increase in extracellular lactate levels in the anterior cingulate cortex (ACC). Inhibition of glycogenolysis and lactate release in the ACC disrupted the persistent, but not acute, inflammation pain induced by CFA, and this effect was reversed by exogenous L-lactate administration. Knocking down the expression of lactate transporters (MCT1, MCT4, or MCT2) also disrupted the long lasting inflammation pain induced by CFA. Moreover, glycogenolysis in the ACC is critical for the induction of molecular changes related to neuronal plasticity, including the induction of phospho- (p-) ERK, p-CREB, and Fos. Taken together, our findings indicate that astrocyte-neuron lactate transport in the ACC is critical for the occurrence of persistent inflammation pain, suggesting a novel mechanism underlying chronic pain.
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Affiliation(s)
- Yin Wang
- Department of Anesthesiology, Taizhou People's Hospital, Taizhou, Jiangsu, China
| | - Yunan Peng
- Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Chenjing Zhang
- Department of Anesthesiology, Taizhou People's Hospital, Taizhou, Jiangsu, China
| | - Xuelong Zhou
- Department of Anesthesiology and Perioperative Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
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Wang X, Ali N, Lin CLG. Emerging role of glutamate in the pathophysiology and therapeutics of Gulf War illness. Life Sci 2021; 280:119609. [PMID: 33991547 DOI: 10.1016/j.lfs.2021.119609] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 05/03/2021] [Accepted: 05/04/2021] [Indexed: 11/20/2022]
Abstract
Gulf War illness (GWI) is a chronic and multi-symptomatic disorder affecting veterans who served in the Gulf War. The commonly reported symptoms in GWI veterans include mood problems, cognitive impairment, muscle and joint pain, migraine/headache, chronic fatigue, gastrointestinal complaints, skin rashes, and respiratory problems. Neuroimaging studies have revealed significant brain structure alterations in GWI veterans, including subcortical atrophy, decreased volume of the hippocampus, reduced total grey and white matter, and increased brain white matter axial diffusivity. These brain changes may contribute to or increase the severities of the GWI-related symptoms. Epidemiological studies have revealed that neurotoxic exposures and stress may be significant contributors to the development of GWI. However, the mechanism underlying how the exposure and stress could contribute to the multi-symptomatic disorder of GWI remains unclear. We and others have demonstrated that rodent models exposed to GW-related agents and stress exhibited higher extracellular glutamate levels, as well as impaired structure and function of glutamatergic synapses. Restoration of the glutamatergic synapses ameliorated the GWI-related pathological and behavioral deficits. Moreover, recent studies showed that a low-glutamate diet reduced multiple symptoms in GWI veterans, suggesting an important role of the glutamatergic system in GWI. Currently, growing evidence has indicated that abnormal glutamate neurotransmission may contribute to the GWI symptoms. This review summarizes the potential roles of glutamate dyshomeostasis and dysfunction of the glutamatergic system in linking the initial cause to the multi-symptomatic outcomes in GWI and suggests the glutamatergic system as a therapeutic target for GWI.
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Affiliation(s)
- Xueqin Wang
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Noor Ali
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Chien-Liang Glenn Lin
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, USA.
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Melchior M, Kuhn P, Poisbeau P. The burden of early life stress on the nociceptive system development and pain responses. Eur J Neurosci 2021; 55:2216-2241. [PMID: 33615576 DOI: 10.1111/ejn.15153] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/27/2021] [Accepted: 02/12/2021] [Indexed: 02/07/2023]
Abstract
For a long time, the capacity of the newborn infant to feel pain was denied. Today it is clear that the nociceptive system, even if still immature, is functional enough in the newborn infant to elicit pain responses. Unfortunately, pain is often present in the neonatal period, in particular in the case of premature infants which are subjected to a high number of painful procedures during care. These are accompanied by a variety of environmental stressors, which could impact the maturation of the nociceptive system. Therefore, the question of the long-term consequences of early life stress is a critical question. Early stressful experience, both painful and non-painful, can imprint the nociceptive system and induce long-term alteration in brain function and nociceptive behavior, often leading to an increase sensitivity and higher susceptibility to chronic pain. Different animal models have been developed to understand the mechanisms underlying the long-term effects of different early life stressful procedures, including pain and maternal separation. This review will focus on the clinical and preclinical data about early life stress and its consequence on the nociceptive system.
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Affiliation(s)
- Meggane Melchior
- Centre National de la Recherche Scientifique and University of Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France
| | - Pierre Kuhn
- Centre National de la Recherche Scientifique and University of Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France.,Service de Médecine et Réanimation du Nouveau-né, Hôpital de Hautepierre, Centre Hospitalier Universitaire de Strasbourg, Strasbourg, France
| | - Pierrick Poisbeau
- Centre National de la Recherche Scientifique and University of Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France
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Abbink MR, Kotah JM, Hoeijmakers L, Mak A, Yvon-Durocher G, van der Gaag B, Lucassen PJ, Korosi A. Characterization of astrocytes throughout life in wildtype and APP/PS1 mice after early-life stress exposure. J Neuroinflammation 2020; 17:91. [PMID: 32197653 PMCID: PMC7083036 DOI: 10.1186/s12974-020-01762-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 02/27/2020] [Indexed: 02/07/2023] Open
Abstract
Background Early-life stress (ES) is an emerging risk factor for later life development of Alzheimer’s disease (AD). We have previously shown that ES modulates amyloid-beta pathology and the microglial response to it in the APPswe/PS1dE9 mouse model. Because astrocytes are key players in the pathogenesis of AD, we studied here if and how ES affects astrocytes in wildtype (WT) and APP/PS1 mice and how these relate to the previously reported amyloid pathology and microglial profile. Methods We induced ES by limiting nesting and bedding material from postnatal days (P) 2–9. We studied in WT mice (at P9, P30, and 6 months) and in APP/PS1 mice (at 4 and 10 months) (i) GFAP coverage, cell density, and complexity in hippocampus (HPC) and entorhinal cortex (EC); (ii) hippocampal gene expression of astrocyte markers; and (iii) the relationship between astrocyte, microglia, and amyloid markers. Results In WT mice, ES increased GFAP coverage in HPC subregions at P9 and decreased it at 10 months. APP/PS1 mice at 10 months exhibited both individual cell as well as clustered GFAP signals. APP/PS1 mice when compared to WT exhibited reduced total GFAP coverage in HPC, which is increased in the EC, while coverage of the clustered GFAP signal in the HPC was increased and accompanied by increased expression of several astrocytic genes. While measured astrocytic parameters in APP/PS1 mice appear not be further modulated by ES, analyzing these in the context of ES-induced alterations to amyloid pathology and microglial shows alterations at both 4 and 10 months of age. Conclusions Our data suggest that ES leads to alterations to the astrocytic response to amyloid-β pathology.
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Affiliation(s)
- Maralinde R Abbink
- Brain Plasticity Group, Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, The Netherlands
| | - Janssen M Kotah
- Brain Plasticity Group, Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, The Netherlands
| | - Lianne Hoeijmakers
- Brain Plasticity Group, Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, The Netherlands
| | - Aline Mak
- Brain Plasticity Group, Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, The Netherlands
| | - Genevieve Yvon-Durocher
- Brain Plasticity Group, Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, The Netherlands
| | - Bram van der Gaag
- Brain Plasticity Group, Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, The Netherlands
| | - Paul J Lucassen
- Brain Plasticity Group, Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, The Netherlands
| | - Aniko Korosi
- Brain Plasticity Group, Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, The Netherlands.
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Abstract
The developmental period constitutes a critical window of sensitivity to stress. Indeed, early-life adversity increases the risk to develop psychiatric diseases, but also gastrointestinal disorders such as the irritable bowel syndrome at adulthood. In the past decade, there has been huge interest in the gut-brain axis, especially as regards stress-related emotional behaviours. Animal models of early-life adversity, in particular, maternal separation (MS) in rodents, demonstrate lasting deleterious effects on both the gut and the brain. Here, we review the effects of MS on both systems with a focus on stress-related behaviours. In addition, we discuss more recent findings showing the impact of gut-directed interventions, including nutrition with pre- and probiotics, illustrating the role played by gut microbiota in mediating the long-term effects of MS. Overall, preclinical studies suggest that nutritional approaches with pro- and prebiotics may constitute safe and efficient strategies to attenuate the effects of early-life stress on the gut-brain axis. Further research is required to understand the complex mechanisms underlying gut-brain interaction dysfunctions after early-life stress as well as to determine the beneficial impact of gut-directed strategies in a context of early-life adversity in human subjects.
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Abbink MR, van Deijk ALF, Heine VM, Verheijen MH, Korosi A. The involvement of astrocytes in early-life adversity induced programming of the brain. Glia 2019; 67:1637-1653. [PMID: 31038797 PMCID: PMC6767561 DOI: 10.1002/glia.23625] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 03/29/2019] [Accepted: 03/29/2019] [Indexed: 12/13/2022]
Abstract
Early‐life adversity (ELA) in the form of stress, inflammation, or malnutrition, can increase the risk of developing psychopathology or cognitive problems in adulthood. The neurobiological substrates underlying this process remain unclear. While neuronal dysfunction and microglial contribution have been studied in this context, only recently the role of astrocytes in early‐life programming of the brain has been appreciated. Astrocytes serve many basic roles for brain functioning (e.g., synaptogenesis, glutamate recycling), and are unique in their capacity of sensing and integrating environmental signals, as they are the first cells to encounter signals from the blood, including hormonal changes (e.g., glucocorticoids), immune signals, and nutritional information. Integration of these signals is especially important during early development, and therefore we propose that astrocytes contribute to ELA induced changes in the brain by sensing and integrating environmental signals and by modulating neuronal development and function. Studies in rodents have already shown that ELA can impact astrocytes on the short and long term, however, a critical review of these results is currently lacking. Here, we will discuss the developmental trajectory of astrocytes, their ability to integrate stress, immune, and nutritional signals from the early environment, and we will review how different types of early adversity impact astrocytes.
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Affiliation(s)
- Maralinde R Abbink
- Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands
| | - Anne-Lieke F van Deijk
- Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit, Amsterdam, The Netherlands
| | - Vivi M Heine
- Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit, Amsterdam, The Netherlands
| | - Mark H Verheijen
- Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit, Amsterdam, The Netherlands
| | - Aniko Korosi
- Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands
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Gegelashvili G, Bjerrum OJ. Glutamate transport system as a key constituent of glutamosome: Molecular pathology and pharmacological modulation in chronic pain. Neuropharmacology 2019; 161:107623. [PMID: 31047920 DOI: 10.1016/j.neuropharm.2019.04.029] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 04/26/2019] [Accepted: 04/28/2019] [Indexed: 01/07/2023]
Abstract
Neural uptake of glutamate is executed by the structurally related members of the SLC1A family of solute transporters: GLAST/EAAT1, GLT-1/EAAT2, EAAC1/EAAT3, EAAT4, ASCT2. These plasma membrane proteins ensure supply of glutamate, aspartate and some neutral amino acids, including glutamine and cysteine, for synthetic, energetic and signaling purposes, whereas effective removal of glutamate from the synaptic cleft shapes excitatory neurotransmission and prevents glutamate toxicity. Glutamate transporters (GluTs) possess also receptor-like properties and can directly initiate signal transduction. GluTs are physically linked to other glutamate signaling-, transporting- and metabolizing molecules (e.g., glutamine transporters SNAT3 and ASCT2, glutamine synthetase, NMDA receptor, synaptic vesicles), as well as cellular machineries fueling the transmembrane transport of glutamate (e.g., ion gradient-generating Na/K-ATPase, glycolytic enzymes, mitochondrial membrane- and matrix proteins, glucose transporters). We designate this supramolecular functional assembly as 'glutamosome'. GluTs play important roles in the molecular pathology of chronic pain, due to the predominantly glutamatergic nature of nociceptive signaling in the spinal cord. Down-regulation of GluTs often precedes or occurs simultaneously with development of pain hypersensitivity. Pharmacological inhibition or gene knock-down of spinal GluTs can induce/aggravate pain, whereas enhancing expression of GluTs by viral gene transfer can mitigate chronic pain. Thus, functional up-regulation of GluTs is turning into a prospective pharmacotherapeutic approach for the management of chronic pain. A number of novel positive pharmacological regulators of GluTs, incl. pyridazine derivatives and β-lactams, have recently been introduced. However, design and development of new analgesics based on this principle will require more precise knowledge of molecular mechanisms underlying physiological or aberrant functioning of the glutamate transport system in nociceptive circuits. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'.
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Affiliation(s)
- Georgi Gegelashvili
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark; Institute of Chemical Biology, Ilia State University, Tbilisi, Georgia.
| | - Ole Jannik Bjerrum
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
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Glutamatergic Signaling Along The Microbiota-Gut-Brain Axis. Int J Mol Sci 2019; 20:ijms20061482. [PMID: 30934533 PMCID: PMC6471396 DOI: 10.3390/ijms20061482] [Citation(s) in RCA: 211] [Impact Index Per Article: 35.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 03/04/2019] [Accepted: 03/21/2019] [Indexed: 12/21/2022] Open
Abstract
A complex bidirectional communication system exists between the gastrointestinal tract and the brain. Initially termed the “gut-brain axis” it is now renamed the “microbiota-gut-brain axis” considering the pivotal role of gut microbiota in maintaining local and systemic homeostasis. Different cellular and molecular pathways act along this axis and strong attention is paid to neuroactive molecules (neurotransmitters, i.e., noradrenaline, dopamine, serotonin, gamma aminobutyric acid and glutamate and metabolites, i.e., tryptophan metabolites), sustaining a possible interkingdom communication system between eukaryota and prokaryota. This review provides a description of the most up-to-date evidence on glutamate as a neurotransmitter/neuromodulator in this bidirectional communication axis. Modulation of glutamatergic receptor activity along the microbiota-gut-brain axis may influence gut (i.e., taste, visceral sensitivity and motility) and brain functions (stress response, mood and behavior) and alterations of glutamatergic transmission may participate to the pathogenesis of local and brain disorders. In this latter context, we will focus on two major gut disorders, such as irritable bowel syndrome and inflammatory bowel disease, both characterized by psychiatric co-morbidity. Research in this area opens the possibility to target glutamatergic neurotransmission, either pharmacologically or by the use of probiotics producing neuroactive molecules, as a therapeutic approach for the treatment of gastrointestinal and related psychiatric disorders.
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Mohammadi EN, Ligon CO, Silos-Santiago A, Ge P, Kurtz C, Higgins C, Hannig G, Greenwood-Van Meerveld B. Linaclotide Attenuates Visceral Organ Crosstalk: Role of Guanylate Cyclase-C Activation in Reversing Bladder-Colon Cross-Sensitization. J Pharmacol Exp Ther 2018; 366:274-281. [PMID: 29784661 PMCID: PMC6034264 DOI: 10.1124/jpet.118.248567] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Accepted: 03/21/2018] [Indexed: 12/15/2022] Open
Abstract
Bladder pain syndrome (BPS) is poorly understood; however, there is a female predominance and comorbidity with irritable bowel syndrome (IBS). Here we test the hypothesis that linaclotide, a guanylate cyclase-C (GC-C) agonist approved for the treatment of IBS with constipation (IBS-C), may represent a novel therapeutic for BPS acting through a mechanism involving an inhibition of visceral organ cross-sensitization. We showed previously that infusion of dilute protamine sulfate (PS) into the bladder increased sensitivity and permeability in the bladder and colon. PS was infused into the bladder of female rats; sensitivity was assessed via application of von Frey filaments applied to the suprapubic area and the frequency of withdrawal responses was recorded. Colonic sensitivity was measured via visceromotor behavioral response to graded pressures of colorectal distension (CRD). Permeability was measured in vitro via transepithelial electrical resistance (TEER) and conductance (G). Linaclotide (3 µg/kg, p.o.) or vehicle was administered daily for 7 days prior to experiments. Rats treated with PS bladder infusion exhibited visceral hyperalgesia, as shown by a significantly higher response frequency to individual von Frey filaments and increased behavioral responses to CRD. Linaclotide attenuated bladder and colonic hyperalgesia to control levels. PS infusion into the bladder increased bladder and colon permeability measured as a decrease in TEER and increased G. Linaclotide significantly inhibited PS-induced colonic hyperpermeability while having no effect on bladder hyperpermeability. Our findings suggest a novel treatment paradigm for GC-C agonism in IBS-C and BPS mediated through a mechanism involving visceral organ crosstalk.
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Affiliation(s)
- Ehsan N Mohammadi
- Oklahoma Center for Neuroscience (E.N.M., C.O.L., B.G.-V.M.), Department of Physiology (B.G.-V.M.), and Veterans Affairs Medical Center (B.G.-V.M.), University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; and Ironwood Pharmaceuticals, Cambridge, Massachusetts (A.S.-S., P.G., C.K., C.H., G.H.)
| | - Casey O Ligon
- Oklahoma Center for Neuroscience (E.N.M., C.O.L., B.G.-V.M.), Department of Physiology (B.G.-V.M.), and Veterans Affairs Medical Center (B.G.-V.M.), University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; and Ironwood Pharmaceuticals, Cambridge, Massachusetts (A.S.-S., P.G., C.K., C.H., G.H.)
| | - Ada Silos-Santiago
- Oklahoma Center for Neuroscience (E.N.M., C.O.L., B.G.-V.M.), Department of Physiology (B.G.-V.M.), and Veterans Affairs Medical Center (B.G.-V.M.), University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; and Ironwood Pharmaceuticals, Cambridge, Massachusetts (A.S.-S., P.G., C.K., C.H., G.H.)
| | - Pei Ge
- Oklahoma Center for Neuroscience (E.N.M., C.O.L., B.G.-V.M.), Department of Physiology (B.G.-V.M.), and Veterans Affairs Medical Center (B.G.-V.M.), University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; and Ironwood Pharmaceuticals, Cambridge, Massachusetts (A.S.-S., P.G., C.K., C.H., G.H.)
| | - Caroline Kurtz
- Oklahoma Center for Neuroscience (E.N.M., C.O.L., B.G.-V.M.), Department of Physiology (B.G.-V.M.), and Veterans Affairs Medical Center (B.G.-V.M.), University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; and Ironwood Pharmaceuticals, Cambridge, Massachusetts (A.S.-S., P.G., C.K., C.H., G.H.)
| | - Carolyn Higgins
- Oklahoma Center for Neuroscience (E.N.M., C.O.L., B.G.-V.M.), Department of Physiology (B.G.-V.M.), and Veterans Affairs Medical Center (B.G.-V.M.), University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; and Ironwood Pharmaceuticals, Cambridge, Massachusetts (A.S.-S., P.G., C.K., C.H., G.H.)
| | - Gerhard Hannig
- Oklahoma Center for Neuroscience (E.N.M., C.O.L., B.G.-V.M.), Department of Physiology (B.G.-V.M.), and Veterans Affairs Medical Center (B.G.-V.M.), University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; and Ironwood Pharmaceuticals, Cambridge, Massachusetts (A.S.-S., P.G., C.K., C.H., G.H.)
| | - Beverley Greenwood-Van Meerveld
- Oklahoma Center for Neuroscience (E.N.M., C.O.L., B.G.-V.M.), Department of Physiology (B.G.-V.M.), and Veterans Affairs Medical Center (B.G.-V.M.), University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; and Ironwood Pharmaceuticals, Cambridge, Massachusetts (A.S.-S., P.G., C.K., C.H., G.H.)
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White Matter Microstructure in Bipolar Disorder Is Influenced by the Interaction between a Glutamate Transporter EAAT1 Gene Variant and Early Stress. Mol Neurobiol 2018; 56:702-710. [DOI: 10.1007/s12035-018-1117-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 05/11/2018] [Indexed: 12/19/2022]
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Genty J, Tetsi Nomigni M, Anton F, Hanesch U. Maternal separation stress leads to resilience against neuropathic pain in adulthood. Neurobiol Stress 2017; 8:21-32. [PMID: 29276736 PMCID: PMC5738238 DOI: 10.1016/j.ynstr.2017.11.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 11/03/2017] [Accepted: 11/21/2017] [Indexed: 12/24/2022] Open
Abstract
Early life stress (ELS) leads to a permanent reprogramming of biochemical stress response cascades that may also be relevant for the processing of chronic pain states such as neuropathy. Despite clinical evidence, little is known about ELS-related vulnerability for neuropathic pain and the possibly underlying etiology. In the framework of experimental studies aimed at investigating the respective relationships we used the established ELS model of maternal separation (MS). Rat dams and neonates were separated for 3 h/day from post-natal day 2–12. At adulthood, noxious mechanical and thermal thresholds were assessed before and during induction of neuropathic pain by chronic constriction injury (CCI). The potential involvement of spinal glutamatergic transmission, glial cells, pro-inflammatory cytokines and growth factors was studied by using qPCR. MS per se did not modify pain thresholds. But, when exposed to neuropathic pain, MS rats exhibited a marked reduction of thermal sensitivity and a delayed development of mechanical allodynia/hyperalgesia when compared to control animals. Also, MS did not alter glucocorticoid receptor mRNA levels, but prevented the CCI-induced down-regulation of NR1 and NR2 sub-units of the NMDA receptor and of the glutamate transporter EAAT3 as observed at 21 days post-surgery. Additionally, CCI-provoked up-regulation of glial cell markers was either prevented (GFAP for astrocytes) or dampened (Iba1 for microglia) by MS. Pro-inflammatory cytokine mRNA expression was either not affected (IL-6) or reduced (IL-1β) by MS shortly after CCI. The growth factors GDNF and NGF were only slightly downregulated 4 days after CCI in the MS-treated animals. The changes in glutamatergic signaling, astroglial and cytokine activation as well as neurotrophin expression could, to some extent, explain these changes in pain behavior. Taken together, the results obtained in the described experimental conditions support the mismatch theory of chronic stress where an early life stress, rather than predisposing individuals to certain pathologies, renders them resilient.
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Affiliation(s)
- Julien Genty
- Laboratory of Neurophysiology, Institute for Health and Behavior, University of Luxembourg, 162a, avenue de la Faïencerie, L-1511, Luxembourg, Luxembourg
| | - Milène Tetsi Nomigni
- Laboratory of Neurophysiology, Institute for Health and Behavior, University of Luxembourg, 162a, avenue de la Faïencerie, L-1511, Luxembourg, Luxembourg
| | - Fernand Anton
- Laboratory of Neurophysiology, Institute for Health and Behavior, University of Luxembourg, 162a, avenue de la Faïencerie, L-1511, Luxembourg, Luxembourg
| | - Ulrike Hanesch
- Laboratory of Neurophysiology, Institute for Health and Behavior, University of Luxembourg, 162a, avenue de la Faïencerie, L-1511, Luxembourg, Luxembourg
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Xu S, Qin B, Shi A, Zhao J, Guo X, Dong L. Oxytocin inhibited stress induced visceral hypersensitivity, enteric glial cells activation, and release of proinflammatory cytokines in maternal separated rats. Eur J Pharmacol 2017; 818:578-584. [PMID: 29162434 DOI: 10.1016/j.ejphar.2017.11.018] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2017] [Revised: 11/13/2017] [Accepted: 11/13/2017] [Indexed: 12/13/2022]
Abstract
Visceral hypersensitivity (VH) is a significant contributor to irritable bowel syndrome (IBS). Oxytocin (OT) possesses analgesic effects on the central nervous system (CNS) and attenuates microglial activation, however, little is known about its peripheral effects and involvement in VH of IBS. Reactive enteric glial cells (EGCs) contributes to abnormal motility in gastrointestinal (GI) diseases. The aim of this study was to evaluate the peripheral use of OT to maintain VH and activation of EGCs through involvement of the Toll-like receptor (TLR) 4/MyD88/NF-κB signaling. After assessing a baseline visceromotor response (VMR) to colorectal distension (CRD), rats were exposed to a 1h water avoidance stress (WAS) session. Before each WAS session, intraperitoneal injection of OT (1mg/kg body weight, in phosphate-buffered saline (PBS)) atosiban (0.5mg/kg body weight, in PBS) or PBS (as a vehicle control, 1ml/kg body weight) was administered. Animas are killed 24h after the last WAS session. EGCs activity, relative OT receptor expression, glial fibrillary acidic protein (GFAP) expression and TLR4/MyD88/NF-κB signaling were evaluated. Neonatal maternal separation (MS) significantly increased the OT receptor expression and enhanced VMR to CRD. WAS improved VMR to CRD only during neonatal MS. OT treatment prevented WAS-induced higher VMRs to CRD, which was reversed by an OT receptor antagonist administration. Compared to the vehicle, OT pre-treated rats reduced EGCs activation, GFAP expression and TLR4/MyD88/NF-κB signaling. We conclude that neonatal MS induces VH and visceral pain in rats. Furthermore, exogenous OT attenuated stress-induced VH and EGCs activation, which was mediated by TLR4/MyD88/NF-κB signaling.
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Affiliation(s)
- Shaoxian Xu
- Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Bin Qin
- Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Ameng Shi
- Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Jing Zhao
- Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Xiaoyan Guo
- Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Lei Dong
- Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
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Jing FC, Zhang J, Feng C, Nian YY, Wang JH, Hu H, Yang BD, Sun XM, Zheng JY, Yin XR. Potential rat model of anxiety-like gastric hypersensitivity induced by sequential stress. World J Gastroenterol 2017; 23:7594-7608. [PMID: 29204059 PMCID: PMC5698252 DOI: 10.3748/wjg.v23.i42.7594] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Revised: 10/04/2017] [Accepted: 10/18/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To establish a rat model of anxiety-like gastric hypersensitivity (GHS) of functional dyspepsia (FD) induced by novel sequential stress.
METHODS Animal pups were divided into two groups from postnatal day 2: controls and the sequential-stress-treated. The sequential-stress-treated group received maternal separation and acute gastric irritation early in life and restraint stress in adulthood; controls were reared undisturbed with their mothers. Rats in both groups were followed to adulthood (8 wk) at which point the anxiety-like behaviors and visceromotor responses to gastric distention (20-100 mmHg) and gastric emptying were tested. Meanwhile, alterations in several anxiety-related brain-stomach modulators including 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA), brain-derived neurotrophic factor (BDNF) and nesfatin-1 in the rat hippocampus, plasma and gastric fundus and the 5-HT1A receptor (5-HT1AR) in the hippocampal CA1 subfield and the mucosa of the gastric fundus were examined.
RESULTS Sequential-stress-treated rats simultaneously demonstrated anxiety-like behaviors and GHS in dose-dependent manner compared with the control group. Although rats in both groups consumed similar amount of solid food, the rate of gastric emptying was lower in the sequential-stress-treated rats than in the control group. Sequential stress significantly decreased the levels of 5-HT (51.91 ± 1.88 vs 104.21 ± 2.88, P < 0.01), GABA (2.38 ± 0.16 vs 5.01 ± 0.13, P < 0.01) and BDNF (304.40 ± 10.16 vs 698.17 ± 27.91, P < 0.01) in the hippocampus but increased the content of nesfatin-1 (1961.38 ± 56.89 vs 1007.50 ± 33.05, P < 0.01) in the same site; significantly decreased the levels of 5-HT (47.82 ± 2.29 vs 89.45 ± 2.61, P < 0.01) and BDNF (257.05 ± 12.89 vs 536.71 ± 20.73, P < 0.01) in the plasma but increased the content of nesfatin-1 in it (1391.75 ± 42.77 vs 737.88 ± 33.15, P < 0.01); significantly decreased the levels of 5-HT (41.15 ± 1.81 vs 89.17 ± 2.31, P < 0.01) and BDNF (226.49 ± 12.10 vs 551.36 ± 16.47, P < 0.01) in the gastric fundus but increased the content of nesfatin-1 in the same site (1534.75 ± 38.52 vs 819.63 ± 38.04, P < 0.01). The expressions of 5-HT1AR in the hippocampal CA1 subfield and the mucosa of the gastric fundus were down-regulated measured by IHC (Optical Density value: Hippocampus 15253.50 ± 760.35 vs 21149.75 ± 834.13; gastric fundus 15865.25 ± 521.24 vs 23865.75 ± 1868.60; P < 0.05, respectively) and WB (0.38 ± 0.01 vs 0.57 ± 0.03, P < 0.01) (n = 8 in each group).
CONCLUSION Sequential stress could induce a potential rat model of anxiety-like GHS of FD, which could be used to research the mechanisms of this intractable disease.
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Affiliation(s)
- Fu-Chun Jing
- Department of Gastroenterology, Second Hospital Affiliated to the Medical School of Xi’an Jiao Tong University, Xi’an 710004, Shaanxi Province, China
- Department of Digestive Diseases, Baoji People’s Hospital Affiliated to the Medical School of Yan’an University, Baoji 721000, Shaanxi Province, China
| | - Jun Zhang
- Department of Gastroenterology, Second Hospital Affiliated to the Medical School of Xi’an Jiao Tong University, Xi’an 710004, Shaanxi Province, China
| | - Chen Feng
- Department of Gastroenterology, Second Hospital Affiliated to the Medical School of Xi’an Jiao Tong University, Xi’an 710004, Shaanxi Province, China
| | - Yuan-Yuan Nian
- Department of Gastroenterology, Second Hospital Affiliated to the Medical School of Xi’an Jiao Tong University, Xi’an 710004, Shaanxi Province, China
| | - Jin-Hai Wang
- Department of Gastroenterology, Second Hospital Affiliated to the Medical School of Xi’an Jiao Tong University, Xi’an 710004, Shaanxi Province, China
| | - Hao Hu
- Department of Pharmacology, Health Science Center, Xi’an Jiao Tong University, Xi’an 710061, Shaanxi Province, China
- Basic Medical Experiment Teaching Center, Health Science Center, Xi’an Jiao Tong University, Xi’an 710061, Shaanxi Province, China
| | - Bao-De Yang
- Department of Pharmacology, Health Science Center, Xi’an Jiao Tong University, Xi’an 710061, Shaanxi Province, China
- Basic Medical Experiment Teaching Center, Health Science Center, Xi’an Jiao Tong University, Xi’an 710061, Shaanxi Province, China
| | - Xiao-Ming Sun
- Department of Pharmacology, Health Science Center, Xi’an Jiao Tong University, Xi’an 710061, Shaanxi Province, China
- Basic Medical Experiment Teaching Center, Health Science Center, Xi’an Jiao Tong University, Xi’an 710061, Shaanxi Province, China
| | - Jian-Yun Zheng
- Department of Pathology, the First Affiliated Hospital of Xi’an Medical University, Xi’an 710077, Shaanxi Province, China
| | - Xiao-Ran Yin
- Department of Gastroenterology, Second Hospital Affiliated to the Medical School of Xi’an Jiao Tong University, Xi’an 710004, Shaanxi Province, China
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Wang J, Tu J, Cao B, Mu L, Yang X, Cong M, Ramkrishnan AS, Chan RH, Wang L, Li Y. Astrocytic l -Lactate Signaling Facilitates Amygdala-Anterior Cingulate Cortex Synchrony and Decision Making in Rats. Cell Rep 2017; 21:2407-2418. [DOI: 10.1016/j.celrep.2017.11.012] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2017] [Revised: 09/30/2017] [Accepted: 11/01/2017] [Indexed: 01/14/2023] Open
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O'Mahony SM, Clarke G, Dinan TG, Cryan JF. Irritable Bowel Syndrome and Stress-Related Psychiatric Co-morbidities: Focus on Early Life Stress. Handb Exp Pharmacol 2017; 239:219-246. [PMID: 28233180 DOI: 10.1007/164_2016_128] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Irritable bowel syndrome is a functional gastrointestinal disorder, with stress playing a major role in onset and exacerbation of symptoms such as abdominal pain and altered bowel movements. Stress-related disorders including anxiety and depression often precede the development of irritable bowel syndrome and vice versa. Stressor exposure during early life has the potential to increase an individual's susceptibility to both irritable bowel syndrome and psychiatric disease indicating that there may be a common origin for these disorders. Moreover, adverse early life events significantly impact upon many of the communication pathways within the brain-gut-microbiota axis, which allows bidirectional interaction between the central nervous system and the gastrointestinal tract. This axis is proposed to be perturbed in irritable bowel syndrome and studies now indicate that dysfunction of this axis is also seen in psychiatric disease. Here we review the co-morbidity of irritable bowel syndrome and psychiatric disease with their common origin in mind in relation to the impact of early life stress on the developing brain-gut-microbiota axis. We also discuss the therapeutic potential of targeting this axis in these diseases.
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Affiliation(s)
- Siobhain M O'Mahony
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland. .,APC Microbiome Institute, University College Cork, Cork, Ireland.
| | - Gerard Clarke
- APC Microbiome Institute, University College Cork, Cork, Ireland.,Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - Timothy G Dinan
- APC Microbiome Institute, University College Cork, Cork, Ireland.,Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - John F Cryan
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.,APC Microbiome Institute, University College Cork, Cork, Ireland
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Luczynski P, Tramullas M, Viola M, Shanahan F, Clarke G, O'Mahony S, Dinan TG, Cryan JF. Microbiota regulates visceral pain in the mouse. eLife 2017. [PMID: 28629511 PMCID: PMC5478269 DOI: 10.7554/elife.25887] [Citation(s) in RCA: 121] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The perception of visceral pain is a complex process involving the spinal cord and higher order brain structures. Increasing evidence implicates the gut microbiota as a key regulator of brain and behavior, yet it remains to be determined if gut bacteria play a role in visceral sensitivity. We used germ-free mice (GF) to assess visceral sensitivity, spinal cord gene expression and pain-related brain structures. GF mice displayed visceral hypersensitivity accompanied by increases in Toll-like receptor and cytokine gene expression in the spinal cord, which were normalized by postnatal colonization with microbiota from conventionally colonized (CC). In GF mice, the volumes of the anterior cingulate cortex (ACC) and periaqueductal grey, areas involved in pain processing, were decreased and enlarged, respectively, and dendritic changes in the ACC were evident. These findings indicate that the gut microbiota is required for the normal visceral pain sensation. DOI:http://dx.doi.org/10.7554/eLife.25887.001 The human gut is home to over 100 trillion microbes collectively known as the gut microbiota. These microbes help us to digest food and absorb the nutrients effectively. A diverse and stable community of gut microbes is believed to be important for good health. Recently, it has also become clear that the microbiota can also influence the brain and how we behave. For example, many studies suggest that gut microbiota can alter how an individual perceives pain, but it is not clear how this works. Rodents are often used in experiments as models of human biology. One of the most frequently used rodent models in studies of gut microbes is the “germ-free” mouse. These mice grow up in laboratory environments that are completely free of microbes, making it possible to study how having no gut microbes affects the health and behaviour of the mice. Luczynski, Tramullas et al. used germ-free mice to study how the gut microbiota influences an animal’s sensitivity to pain. The experiments show that, compared to mice with normal gut microbiota, the germ-free mice were more sensitive to pain from internal organs especially the gut. These mice also produced larger amounts of specific proteins involved in immune responses, which contributed to the animal’s increased sensitivity to pain. Allowing the germ-free mice to be colonised with gut microbes could reverse these changes. The experiments also show that the germ-free mice had changes in the size of two areas of the brain involved in sensing pain: an area called the anterior cingulate cortex was smaller, while the periaqueductal grey region was enlarged. There were also differences in individual nerve cells within the anterior cingulate cortex compared to normal mice. The findings of Luczynski, Tramullas et al. reinforce the idea that the gut microbiota is involved in the sensation of pain from internal organs, and show that hypersensitivity to this form of pain can be reversed later in life by colonising the gut with microbes. Continuing to study the impact of microbes on this type of pain could aid the development of new therapies for the treatment of pain disorders in humans. DOI:http://dx.doi.org/10.7554/eLife.25887.002
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Affiliation(s)
| | - Monica Tramullas
- APC Microbiome Institute, University College Cork, Cork, Ireland
| | - Maria Viola
- APC Microbiome Institute, University College Cork, Cork, Ireland
| | - Fergus Shanahan
- APC Microbiome Institute, University College Cork, Cork, Ireland
| | - Gerard Clarke
- APC Microbiome Institute, University College Cork, Cork, Ireland.,Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - Siobhain O'Mahony
- APC Microbiome Institute, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - Timothy G Dinan
- APC Microbiome Institute, University College Cork, Cork, Ireland.,Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - John F Cryan
- APC Microbiome Institute, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
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25
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Le Coz GM, Genty J, Anton F, Hanesch U. Chronic Social Stress Time-Dependently Affects Neuropathic Pain-Related Cold Allodynia and Leads to Altered Expression of Spinal Biochemical Mediators. Front Behav Neurosci 2017; 11:70. [PMID: 28536509 PMCID: PMC5422477 DOI: 10.3389/fnbeh.2017.00070] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2017] [Accepted: 04/07/2017] [Indexed: 12/17/2022] Open
Abstract
Clinical data have shown that chronic exposure to stress may be accompanied by an enhancement of inflammation-related pain sensitivity. In this context, little is however known on the impact of stress on neuropathic pain. In the present study we addressed this issue by combining the chronic constriction injury (CCI) model with an ongoing social stress (OSS) paradigm. Cold plate and von Frey tests were performed in 48 rats divided into four groups: OSS exposed to OSS, CCI subjected to chronic nerve constriction, OSS+CCI with a combination of neuropathy and stress and CON, a control group lacking any manipulation. While we did not observe any stress-related differences in mechanical sensitivity throughout the observation period, CCI rats were more sensitive to cold stimulation than OSS+CCI in the initial phase of neuropathy. A switch was observed at a later stage, leading to a hypersensitivity of the OSS+CCI compared to the CCI rats. At this time point we investigated the spinal mRNA expression of neuron and glia related molecules potentially involved in neuropathic pain and stress. The combination of psychosocial stress and neuropathic pain seemed to enhance glial cell activation, pro-inflammatory cytokine and neurotrophic factor mRNA levels, rather than glutamatergic transmission. Our data show that long lasting social stress may lead to time-dependent alteration of neuropathy-related cold pain sensitivity while mechanically-induced pain remains unchanged.
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Affiliation(s)
- Glenn-Marie Le Coz
- Laboratory of Neurophysiology and Psychobiology, Institute for Health and Behavior, University of LuxembourgLuxembourg, Luxembourg
| | - Julien Genty
- Laboratory of Neurophysiology and Psychobiology, Institute for Health and Behavior, University of LuxembourgLuxembourg, Luxembourg
| | - Fernand Anton
- Laboratory of Neurophysiology and Psychobiology, Institute for Health and Behavior, University of LuxembourgLuxembourg, Luxembourg
| | - Ulrike Hanesch
- Laboratory of Neurophysiology and Psychobiology, Institute for Health and Behavior, University of LuxembourgLuxembourg, Luxembourg
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26
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He YQ, Lang XQ, Lin L, Ji L, Yuan XY, Chen Q, Ran YM, Chen HS, Li L, Wang JM, Wang ZG, Gregersen H, Zou DW, Liang HP, Yang M. P2X3 receptor-mediated visceral hyperalgesia and neuronal sensitization following exposure to PTSD-like stress in the dorsal root ganglia of rats. Neurogastroenterol Motil 2017; 29. [PMID: 27781340 DOI: 10.1111/nmo.12976] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Accepted: 09/22/2016] [Indexed: 12/18/2022]
Abstract
BACKGROUND Patients with posttraumatic stress disorder (PTSD) often share co-morbidity with chronic pain conditions. Recent studies suggest a role of P2X3 receptors and ATP signaling in pain conditions. However, the underlying mechanisms of visceral hyperalgesia following exposure to PTSD-like stress conditions remain unclarified. METHODS The behavior and hormones relevant for PTSD were studied. Visceromotor responses (VMR) and the abdominal withdrawal reflexes (AWR) to colorectal distention (CRD) were recorded to determine P2X3-receptor-mediated alteration of hyperalgesia following single-prolonged stress (SPS) exposure. Immunofluorescence, Western blotting, and patch-clamp were used. KEY RESULTS The escape latency, adrenocorticotropic hormone and cortisol were increased on days 7-14. Visceromotor responses and AWR was reduced at day 1 in SPS rats but increased to higher levels than in controls after exposure to day 7. Intrathecal administration of the P2X3-receptor antagonist TNP-ATP abolished the CRD response. Based on immunofluorescence and Western blotting analysis, SPS-treated rats exhibited reduced P2X3 expression in dorsal root ganglia (DRG) after day 1 compared with controls. P2X3 expression in DRG was enhanced on day 7 after SPS and the increase of the P2X3 expression was maintained on day 14 and 21 compared with controls. The P2X3-receptor agonist α,β-me ATP (10 μM) induced a fast desensitizing inward current in DRG neurons of both control and SPS-treated rats. The average peak current densities in SPS-treated group were increased 3.6-fold. TNP-ATP (100 nM) markedly blocked all fast α,β-me ATP-induced inward currents in the DRG neurons both in control and SPS-treated rats. CONCLUSIONS & INFERENCES The data indicate an important role of P2X3 signaling in visceral hyperalgesia following PTSD-like stress.
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Affiliation(s)
- Y-Q He
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Gastroenterology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - X-Q Lang
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Gastroenterology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - L Lin
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Gastroenterology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - L Ji
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Gastroenterology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - X-Y Yuan
- Department of Gastroenterology, The Ninth People's Hospital of Chongqing, Chongqing, China
| | - Q Chen
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Gastroenterology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Y-M Ran
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Gastroenterology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - H-S Chen
- Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Chongqing, China
| | - L Li
- Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China
| | - J-M Wang
- Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Z-G Wang
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Gastroenterology, Daping Hospital, Third Military Medical University, Chongqing, China.,Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China
| | - H Gregersen
- GIOME and the Key Laboratory for Biorheological Science and Technology of Ministry of Education, Bioengineering College of Chongqing University, Chongqing, China
| | - D-W Zou
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - H-P Liang
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Gastroenterology, Daping Hospital, Third Military Medical University, Chongqing, China.,Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China
| | - M Yang
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Gastroenterology, Daping Hospital, Third Military Medical University, Chongqing, China.,Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China
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28
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Glutamate Transport System as a Novel Therapeutic Target in Chronic Pain: Molecular Mechanisms and Pharmacology. ADVANCES IN NEUROBIOLOGY 2017; 16:225-253. [PMID: 28828613 DOI: 10.1007/978-3-319-55769-4_11] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The vast majority of peripheral neurons sensing noxious stimuli and conducting pain signals to the dorsal horn of the spinal cord utilize glutamate as a chemical transmitter of excitation. High-affinity glutamate transporter subtypes GLAST/EAAT1, GLT1/EAAT2, EAAC1/EAAT3, and EAAT4, differentially expressed on sensory neurons, postsynaptic spinal interneurons, and neighboring glia, ensure fine modulation of glutamate neurotransmission in the spinal cord. The glutamate transport system seems to play important roles in molecular mechanisms underlying chronic pain and analgesia. Downregulation of glutamate transporters (GluTs) often precedes or occurs simultaneously with development of hypersensitivity to thermal or tactile stimuli in various models of chronic pain. Moreover, antisense knockdown or pharmacological inhibition of these membrane proteins can induce or aggravate pain. In contrast, upregulation of GluTs by positive pharmacological modulators or by viral gene transfer to the spinal cord can reverse the development of such pathological hypersensitivity. Furthermore, some multi-target drugs displaying analgesic properties (e.g., tricyclic antidepressant amitriptyline, riluzole, anticonvulsant valproate, tetracycline antibiotic minocycline, β-lactam antibiotic ceftriaxone and its structural analog devoid of antibacterial activity, clavulanic acid) can significantly increase the spinal glutamate uptake. Thus, mounting evidence points at GluTs as prospective therapeutic target for chronic pain treatment. However, design and development of new analgesics based on the modulation of glutamate uptake will require more precise knowledge of molecular mechanisms underlying physiological or aberrant functioning of this transport system in the spinal cord.
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Hoban A, Moloney R, Golubeva A, McVey Neufeld K, O’Sullivan O, Patterson E, Stanton C, Dinan T, Clarke G, Cryan J. Behavioural and neurochemical consequences of chronic gut microbiota depletion during adulthood in the rat. Neuroscience 2016; 339:463-477. [DOI: 10.1016/j.neuroscience.2016.10.003] [Citation(s) in RCA: 192] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 09/05/2016] [Accepted: 10/02/2016] [Indexed: 12/22/2022]
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30
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Zhou XP, Sha J, Huang L, Li TN, Zhang RR, Tang MD, Lin L, Li XL. Nesfatin-1/NUCB2 in the amygdala influences visceral sensitivity via glucocorticoid and mineralocorticoid receptors in male maternal separation rats. Neurogastroenterol Motil 2016; 28:1545-53. [PMID: 27380730 DOI: 10.1111/nmo.12853] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 04/17/2016] [Indexed: 12/21/2022]
Abstract
BACKGROUND Nesfatin-1, a recently identified satiety molecule derived from nucleobindin 2 (NUCB2), is associated with visceral hypersensitivity in rats and is expressed in the amygdala. We tested the hypothesis that nesfatin-1 expression in the amygdala is involved in the pathogenesis of irritable bowel syndrome (IBS) visceral hypersensitivity. METHODS An animal model of IBS-like visceral hypersensitivity was established using maternal separation (MS) during postnatal days 2-16. The role of nesfatin-1 in the amygdala on visceral sensitivity was evaluated. KEY RESULTS Rats subjected to MS showed a significantly increased mean abdominal withdrawal reflex (AWR) score and electromyographic (EMG) activity at 40, 60, and 80 mmHg colorectal distension. Plasma concentrations of nesfatin-1 and corticosterone were significantly higher than in non-handled (NH) rats. mRNA and protein expression of nesfatin-1/NUCB2 in the amygdala were increased in MS rats, but not in NH rats. In MS rats, AWR scores and EMG activity were significantly decreased after anti-nesfatin-1/NUCB2 injection. In normal rats, mean AWR score, EMG activity, and corticosterone expression were significantly increased after nesfatin-1 injection into the amygdala. Nesfatin-1-induced visceral hypersensitivity was abolished following application of glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) antagonists. CONCLUSIONS & INFERENCES Elevated expression of nesfatin-1/NUCB2 in the amygdala in MS rats suggests a potential role in the pathogenesis of visceral hypersensitivity, which could potentially take place via activation of GR and MR signaling pathways.
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Affiliation(s)
- X-P Zhou
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Third People's Hospital of Zigong, Zigong, Sichuan, China
| | - J Sha
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - L Huang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - T-N Li
- Department of PET/CT, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
| | - R-R Zhang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - M-D Tang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - L Lin
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - X-L Li
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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31
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Sajjad J, Felice VD, Golubeva AV, Cryan JF, O’Mahony SM. Sex-dependent activity of the spinal excitatory amino acid transporter: Role of estrous cycle. Neuroscience 2016; 333:311-9. [DOI: 10.1016/j.neuroscience.2016.07.036] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Revised: 06/28/2016] [Accepted: 07/20/2016] [Indexed: 02/07/2023]
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32
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Filpa V, Moro E, Protasoni M, Crema F, Frigo G, Giaroni C. Role of glutamatergic neurotransmission in the enteric nervous system and brain-gut axis in health and disease. Neuropharmacology 2016; 111:14-33. [PMID: 27561972 DOI: 10.1016/j.neuropharm.2016.08.024] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Revised: 07/18/2016] [Accepted: 08/18/2016] [Indexed: 02/07/2023]
Abstract
Several studies have been carried out in the last 30 years in the attempt to clarify the possible role of glutamate as a neurotransmitter/neuromodulator in the gastrointestinal tract. Such effort has provided immunohistochemical, biomolecular and functional data suggesting that the entire glutamatergic neurotransmitter machinery is present in the complex circuitries of the enteric nervous system (ENS), which participates to the local coordination of gastrointestinal functions. Glutamate is also involved in the regulation of the brain-gut axis, a bi-directional connection pathway between the central nervous system (CNS) and the gut. The neurotransmitter contributes to convey information, via afferent fibers, from the gut to the brain, and to send appropriate signals, via efferent fibers, from the brain to control gut secretion and motility. In analogy with the CNS, an increasing number of studies suggest that dysregulation of the enteric glutamatergic neurotransmitter machinery may lead to gastrointestinal dysfunctions. On the whole, this research field has opened the possibility to find new potential targets for development of drugs for the treatment of gastrointestinal diseases. The present review analyzes the more recent literature on enteric glutamatergic neurotransmission both in physiological and pathological conditions, such as gastroesophageal reflux, gastric acid hypersecretory diseases, inflammatory bowel disease, irritable bowel syndrome and intestinal ischemia/reperfusion injury.
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Affiliation(s)
- Viviana Filpa
- Department of Clinical and Experimental Medicine, University of Insubria, via H. Dunant 5, I-21100 Varese, Italy
| | - Elisabetta Moro
- Department of Internal Medicine and Therapeutics, Section of Pharmacology, via Ferrata 9, I-27100 Pavia, Italy
| | - Marina Protasoni
- Department of Surgical and Morphological Sciences, University of Insubria, via F. Guicciardini 9, I-21100 Varese, Italy
| | - Francesca Crema
- Department of Internal Medicine and Therapeutics, Section of Pharmacology, via Ferrata 9, I-27100 Pavia, Italy
| | - Gianmario Frigo
- Department of Internal Medicine and Therapeutics, Section of Pharmacology, via Ferrata 9, I-27100 Pavia, Italy
| | - Cristina Giaroni
- Department of Clinical and Experimental Medicine, University of Insubria, via H. Dunant 5, I-21100 Varese, Italy
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33
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Fuentes IM, Walker NK, Pierce AN, Holt BR, Di Silvestro ER, Christianson JA. Neonatal maternal separation increases susceptibility to experimental colitis and acute stress exposure in male mice. IBRO Rep 2016; 1:10-18. [PMID: 28164167 PMCID: PMC5289700 DOI: 10.1016/j.ibror.2016.07.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Experiencing early life stress can result in maladjusted stress response via dysregulation of the hypothalamic-pituitary-adrenal axis and serves as a risk factor for developing chronic pelvic pain disorders. We investigated whether neonatal maternal separation (NMS) would increase susceptibility to experimental colitis or exposure to acute or chronic stress. Male mice underwent NMS from postnatal day 1-21 and as adults were assessed for open field behavior, hindpaw sensitivity, and visceromotor response (VMR) to colorectal distension (CRD). VMR was also measured before and after treatment with intracolonic trinitrobenzene sulfonic acid (TNBS) or exposure to acute or chronic water avoidance stress (WAS). Myeloperoxidase (MPO) activity, proinflammatory gene and corticotropin-releasing factor (CRF) receptor expression were measured in distal colon. Baseline VMR was not affected by NMS, but undergoing CRD increased anxiety-like behaviors and mechanical hindpaw sensitivity of NMS mice. Treatment with TNBS dose-dependently decreased body weight and survival only in NMS mice. Following TNBS treatment, IL-6 and artemin mRNA levels were decreased in the distal colon of NMS mice, despite increased MPO activity. A single WAS exposure increased VMR during CRD in NMS mice and increased IL-6 mRNA and CRF2 protein levels in the distal colon of naïve mice, whereas CRF2 protein levels were heightened in NMS colon both at baseline and post-WAS exposure. Taken together, these results suggest that NMS in mice disrupts inflammatory- and stress-induced gene expression in the colon, potentially contributing towards an exaggerated response to specific stressors later in life.
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Affiliation(s)
- Isabella M Fuentes
- Department of Anatomy and Cell Biology, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160
| | - Natalie K Walker
- Department of Anatomy and Cell Biology, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160
| | - Angela N Pierce
- Department of Anatomy and Cell Biology, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160
| | - Briana R Holt
- Department of Anatomy and Cell Biology, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160
| | - Elizabeth R Di Silvestro
- Department of Anatomy and Cell Biology, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160
| | - Julie A Christianson
- Department of Anatomy and Cell Biology, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160
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34
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Moloney RD, Sajjad J, Foley T, Felice VD, Dinan TG, Cryan JF, O'Mahony SM. Estrous cycle influences excitatory amino acid transport and visceral pain sensitivity in the rat: effects of early-life stress. Biol Sex Differ 2016; 7:33. [PMID: 27429736 PMCID: PMC4946195 DOI: 10.1186/s13293-016-0086-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 07/01/2016] [Indexed: 01/26/2023] Open
Abstract
Background Early-life stress (ELS) is a recognized risk factor for chronic pain disorders, and females appear to be more sensitive to the negative effects of stress. Moreover, estrous cycle-related fluctuations in estrogen levels have been linked with alternating pain sensitivity. Aberrant central circuitry involving both the anterior cingulate cortex (ACC) and the lumbosacral spinal cord has also been implicated in the modulation of visceral pain in clinical and preclinical studies. Here we further investigate changes in visceral pain sensitivity and central glutamatergic systems in rats with respect to estrous cycle and ELS. Methods We investigated visceral sensitivity in adult female Sprague-Dawley rats, which had undergone maternal separation (MS) in early life or remained non-separated (NS), by performing colorectal distension (CRD). We also assessed excitatory amino acid uptake through excitatory amino acid transporters (EAATs) in the lumbosacral spinal cord and ACC. Results NS animals in proestrus and estrus exhibited reduced EAAT uptake and decreased threshold to CRD. Moreover, total pain behaviors were increased in these stages. MS rats exhibited lower pain thresholds and higher total pain behaviors to CRD across all stages of the estrous cycle. Interestingly, cortical EAAT function in MS rats was inhibited in the low estrogen state—an effect completely opposite to that seen in NS rats. Conclusions This data confirms that estrous cycle and ELS are significant factors in visceral sensitivity and fluctuations in EAAT function may be a perpetuating factor mediating central sensitization.
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Affiliation(s)
- Rachel D Moloney
- Laboratory of Neurogastroenterology, APC Microbiome Institute, University College Cork, Cork, Ireland.,Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland.,Present Address: Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK USA
| | - Jahangir Sajjad
- Department of Anatomy and Neuroscience, University College Cork, Office 4.113, Western Gateway Building, Cork, Ireland
| | - Tara Foley
- Department of Anatomy and Neuroscience, University College Cork, Office 4.113, Western Gateway Building, Cork, Ireland
| | - Valeria D Felice
- Laboratory of Neurogastroenterology, APC Microbiome Institute, University College Cork, Cork, Ireland
| | - Timothy G Dinan
- Laboratory of Neurogastroenterology, APC Microbiome Institute, University College Cork, Cork, Ireland.,Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - John F Cryan
- Laboratory of Neurogastroenterology, APC Microbiome Institute, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Office 4.113, Western Gateway Building, Cork, Ireland
| | - Siobhain M O'Mahony
- Laboratory of Neurogastroenterology, APC Microbiome Institute, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Office 4.113, Western Gateway Building, Cork, Ireland
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35
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Burke NN, Finn DP, McGuire BE, Roche M. Psychological stress in early life as a predisposing factor for the development of chronic pain: Clinical and preclinical evidence and neurobiological mechanisms. J Neurosci Res 2016; 95:1257-1270. [DOI: 10.1002/jnr.23802] [Citation(s) in RCA: 120] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 05/13/2016] [Accepted: 06/07/2016] [Indexed: 12/13/2022]
Affiliation(s)
- Nikita N. Burke
- Physiology, School of Medicine, National University of Ireland; Galway Ireland
- Centre for Pain Research and Galway Neuroscience Centre, NCBES, National University of Ireland; Galway Ireland
| | - David P. Finn
- Centre for Pain Research and Galway Neuroscience Centre, NCBES, National University of Ireland; Galway Ireland
- Pharmacology and Therapeutics, School of Medicine, National University of Ireland; Galway Ireland
| | - Brian E. McGuire
- Centre for Pain Research and Galway Neuroscience Centre, NCBES, National University of Ireland; Galway Ireland
- Psychology, National University of Ireland; Galway Ireland
| | - Michelle Roche
- Physiology, School of Medicine, National University of Ireland; Galway Ireland
- Centre for Pain Research and Galway Neuroscience Centre, NCBES, National University of Ireland; Galway Ireland
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Tramullas M, Finger BC, Dinan TG, Cryan JF. Obesity Takes Its Toll on Visceral Pain: High-Fat Diet Induces Toll-Like Receptor 4-Dependent Visceral Hypersensitivity. PLoS One 2016; 11:e0155367. [PMID: 27159520 PMCID: PMC4861320 DOI: 10.1371/journal.pone.0155367] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2016] [Accepted: 04/27/2016] [Indexed: 12/30/2022] Open
Abstract
Exposure to high-fat diet induces both, peripheral and central alterations in TLR4 expression. Moreover, functional TLR4 is required for the development of high-fat diet-induced obesity. Recently, central alterations in TLR4 expression have been associated with the modulation of visceral pain. However, it remains unknown whether there is a functional interaction between the role of TLR4 in diet-induced obesity and in visceral pain. In the present study we investigated the impact of long-term exposure to high-fat diet on visceral pain perception and on the levels of TLR4 and Cd11b (a microglial cell marker) protein expression in the prefrontal cortex (PFC) and hippocampus. Peripheral alterations in TLR4 were assessed following the stimulation of spleenocytes with the TLR4-agonist LPS. Finally, we evaluated the effect of blocking TLR4 on visceral nociception, by administering TAK-242, a selective TLR4-antagonist. Our results demonstrated that exposure to high-fat diet induced visceral hypersensitivity. In parallel, enhanced TLR4 expression and microglia activation were found in brain areas related to visceral pain, the PFC and the hippocampus. Likewise, peripheral TLR4 activity was increased following long-term exposure to high-fat diet, resulting in an increased level of pro-inflammatory cytokines. Finally, TLR4 blockage counteracted the hyperalgesic phenotype present in mice fed on high-fat diet. Our data reveal a role for TLR4 in visceral pain modulation in a model of diet-induced obesity, and point to TLR4 as a potential therapeutic target for the development of drugs to treat visceral hypersensitivity present in pathologies associated to fat diet consumption.
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Affiliation(s)
- Mónica Tramullas
- APC Microbiome Institute, University College Cork, Cork, Ireland
- * E-mail:
| | | | - Timothy G. Dinan
- APC Microbiome Institute, University College Cork, Cork, Ireland
- Department of Psychiatry & Neurobehavioural Science, University College Cork, Cork, Ireland
| | - John F. Cryan
- APC Microbiome Institute, University College Cork, Cork, Ireland
- Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland
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Tran L, Schulkin J, Ligon CO, Greenwood-Van Meerveld B. Epigenetic modulation of chronic anxiety and pain by histone deacetylation. Mol Psychiatry 2015; 20:1219-31. [PMID: 25288139 DOI: 10.1038/mp.2014.122] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Revised: 08/01/2014] [Accepted: 08/21/2014] [Indexed: 12/17/2022]
Abstract
Prolonged exposure of the central amygdala (CeA) to elevated corticosteroids (CORT) facilitates long-term anxiety and pain through activation of glucocorticoid receptors (GRs) and corticotropin-releasing factor (CRF). However, the mechanisms maintaining these responses are unknown. Since chronic phenotypes can be sustained by epigenetic mechanisms, including histone modifications such as deacetylation, we tested the hypothesis that histone deacetylation contributes to the maintenance of chronic anxiety and pain induced by prolonged exposure of the CeA to CORT. We found that bilateral infusions of a histone deacetylase inhibitor into the CeA attenuated anxiety-like behavior as well as somatic and visceral hypersensitivity resulting from elevated CORT exposure. Moreover, we delineated a novel pathway through which histone deacetylation could contribute to CORT regulation of GR and subsequent CRF expression in the CeA. Specifically, deacetylation of histone 3 at lysine 9 (H3K9), through the coordinated action of the NAD+-dependent protein deacetylase sirtuin-6 (SIRT6) and nuclear factor kappa B (NFκB), sequesters GR expression leading to disinhibition of CRF. Our results indicate that epigenetic programming in the amygdala, specifically histone modifications, is important in the maintenance of chronic anxiety and pain.
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Affiliation(s)
- L Tran
- Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
| | - J Schulkin
- Department of Neuroscience, Georgetown University, Washington, DC, USA
| | - C O Ligon
- Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
| | - B Greenwood-Van Meerveld
- Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.,V.A. Medical Center, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.,Department of Physiology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
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Abstract
We delineate perspectives for the design and discovery of antiepileptic drugs (AEDs) with fewer side effects by focusing on astroglial modulation of spatiotemporal seizure dynamics. It is now recognized that the major inhibitory neurotransmitter of the brain, γ-aminobutyric acid (GABA), can be released through the reversal of astroglial GABA transporters. Synaptic spillover and subsequent glutamate (Glu) uptake in neighboring astrocytes evoke replacement of extracellular Glu for GABA, driving neurons away from the seizure threshold. Attenuation of synaptic signaling by this negative feedback through the interplay of Glu and GABA transporters of adjacent astroglia can result in shortened seizures. By contrast, long-range activation of astroglia through gap junctions may promote recurrent seizures on the model of pharmacoresistant temporal lobe epilepsy. From their first detection to our current understanding, we identify various targets that shape both short- and long-range neuro-astroglia coupling, as these are manifest in epilepsy phenomena and in the associated research promotions of AED.
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Affiliation(s)
- Julianna Kardos
- Functional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary
| | - Zsolt Szabó
- Functional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary
| | - László Héja
- Functional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary
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Fitzgibbon M, Finn DP, Roche M. High Times for Painful Blues: The Endocannabinoid System in Pain-Depression Comorbidity. Int J Neuropsychopharmacol 2015; 19:pyv095. [PMID: 26342110 PMCID: PMC4815466 DOI: 10.1093/ijnp/pyv095] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 08/17/2015] [Indexed: 01/06/2023] Open
Abstract
Depression and pain are two of the most debilitating disorders worldwide and have an estimated cooccurrence of up to 80%. Comorbidity of these disorders is more difficult to treat, associated with significant disability and impaired health-related quality of life than either condition alone, resulting in enormous social and economic cost. Several neural substrates have been identified as potential mediators in the association between depression and pain, including neuroanatomical reorganization, monoamine and neurotrophin depletion, dysregulation of the hypothalamo-pituitary-adrenal axis, and neuroinflammation. However, the past decade has seen mounting evidence supporting a role for the endogenous cannabinoid (endocannabinoid) system in affective and nociceptive processing, and thus, alterations in this system may play a key role in reciprocal interactions between depression and pain. This review will provide an overview of the preclinical evidence supporting an interaction between depression and pain and the evidence supporting a role for the endocannabinoid system in this interaction.
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Affiliation(s)
| | | | - Michelle Roche
- Physiology (Ms Fitzgibbon and Dr Roche), and Pharmacology and Therapeutics (Dr Finn), School of Medicine, Galway Neuroscience Centre and Centre for Pain Research (Ms Fitzgibbon, Dr Finn, and Dr Roche), National Centre for Biomedical Engineering Science, National University of Ireland Galway, Ireland.
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40
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Enhancing glutamatergic transmission during adolescence reverses early-life stress-induced deficits in the rewarding effects of cocaine in rats. Neuropharmacology 2015; 99:168-76. [PMID: 26187394 DOI: 10.1016/j.neuropharm.2015.07.012] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Revised: 07/06/2015] [Accepted: 07/11/2015] [Indexed: 12/20/2022]
Abstract
Adolescence marks a critical time when the brain is highly susceptible to pathological insult yet also uniquely amenable to therapeutic intervention. It is during adolescence that the onset of the majority of psychiatric disorders, including substance use disorder (SUDs), occurs. It has been well established that stress, particularly during early development, can contribute to the pathological changes which contribute to the development of SUDs. Glutamate as the main excitatory neurotransmitter in the mammalian CNS plays a key role in various physiological processes, including reward function, and in mediating the effects of psychological stress. We hypothesised impairing glutamatergic signalling during the key adolescent period would attenuate early-life stress induced impaired reward function. To test this, we induced early-life stress in male rats using the maternal-separation procedure. During the critical adolescent period (PND25-46) animals were treated with the glutamate transporter activator, riluzole, or the NMDA receptor antagonist, memantine. Adult reward function was assessed using voluntary cocaine intake measured via intravenous self-administration. We found that early-life stress in the form of maternal-separation impaired reward function, reducing the number of successful cocaine-infusions achieved during the intravenous self-administration procedure as well impairing drug-induced reinstatement of cocaine-taking behaviour. Interestingly, riluzole and memantine treatment reversed this stress-induced impairment. These data suggest that reducing glutamatergic signalling may be a viable therapeutic strategy for treating vulnerable individuals at risk of developing SUDs including certain adolescent populations, particularly those which may have experienced trauma during early-life.
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Fujikawa Y, Tominaga K, Tanaka F, Tanigawa T, Watanabe T, Fujiwara Y, Arakawa T. Enteric glial cells are associated with stress-induced colonic hyper-contraction in maternally separated rats. Neurogastroenterol Motil 2015; 27:1010-23. [PMID: 25960044 DOI: 10.1111/nmo.12577] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 04/05/2015] [Indexed: 12/20/2022]
Abstract
BACKGROUND Enteric glial cells (EGCs) play important roles in enteric integrity and regulation of gastrointestinal function. However, whether EGCs undergo pathophysiological changes in stress-associated gastrointestinal disorders is unknown. We investigated structural and functional alterations in colonic EGCs and their roles in colonic contraction in an irritable bowel syndrome (IBS) model. METHODS As a chronic stress, male Wistar rats underwent 3-h maternal separation during postnatal days 2-14. As an acute stress, we used water-immersion stress (4 h) in adulthood (at 8 weeks). We quantitatively and morphologically evaluated enteric neurons and EGCs using whole-mount longitudinal muscle-myenteric plexus preparations. Colonic contraction was analyzed with electrical field stimulation (EFS). KEY RESULTS Glial fibrillary acidic protein (GFAP) expression and the number of total, cholinergic, and nitrergic neurons were unchanged in maternally separated rats with acute stress (combined stress: an IBS model) compared with controls. However, the density of GFAP-positive EGC processes that apparently overlapped with the neurons and the extent of bulbous swelling of terminals increased according to the stress intensity: control, acute stress, maternal separation, and combined stress. EFS-induced colonic contractions were significantly greater in the combined stress rats than in controls. Higher dose of fluorocitrate, a selective inhibitor of EGC metabolism, was required to inhibit both EFS-induced contraction and EGCs activation in the combined stress rats than in controls. CONCLUSIONS & INFERENCES Colonic EGCs exhibited structural alterations according to the stress intensity. EGCs were associated with stress-induced colonic hyper-contraction in the combined stress rats, which may underlie the pathogenesis of IBS.
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Affiliation(s)
- Y Fujikawa
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - K Tominaga
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - F Tanaka
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - T Tanigawa
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - T Watanabe
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Y Fujiwara
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - T Arakawa
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
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42
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Greenwood-Van Meerveld B, Prusator DK, Johnson AC. Animal models of gastrointestinal and liver diseases. Animal models of visceral pain: pathophysiology, translational relevance, and challenges. Am J Physiol Gastrointest Liver Physiol 2015; 308:G885-903. [PMID: 25767262 DOI: 10.1152/ajpgi.00463.2014] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Accepted: 03/11/2015] [Indexed: 02/08/2023]
Abstract
Visceral pain describes pain emanating from the thoracic, pelvic, or abdominal organs. In contrast to somatic pain, visceral pain is generally vague, poorly localized, and characterized by hypersensitivity to a stimulus such as organ distension. Animal models have played a pivotal role in our understanding of the mechanisms underlying the pathophysiology of visceral pain. This review focuses on animal models of visceral pain and their translational relevance. In addition, the challenges of using animal models to develop novel therapeutic approaches to treat visceral pain will be discussed.
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Affiliation(s)
- Beverley Greenwood-Van Meerveld
- Veterans Affairs Medical Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; and Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Dawn K Prusator
- Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Anthony C Johnson
- Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
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Zhou XP, Huang L, Li XL, Lin L. Effect of neonatal maternal separation on serum level of nesfatin-1 in rats. Shijie Huaren Xiaohua Zazhi 2015; 23:2104-2110. [DOI: 10.11569/wcjd.v23.i13.2104] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the effect of neonatal maternal separation on the concentration of serum nesfatin-1 in rats.
METHODS: Newborn male Sprague-Dawley rats were randomly divided into either a maternal separation group or a control group. Rats in the maternal separation group received maternal separation from postnatal days 2-15. At the 8th postnatal week, the abdominal withdrawal reflex (AWR) and electromyographic (EMG) amplitude of the external oblique muscle in response to graded colorectal distension (CRD) were examined. The levels of serum nesfatin-1 and glucocorticoid were detected using ELISA.
RESULTS: At the 8th postnatal week, the body weight of rats in the maternal separation group was significantly lower than that in the normal control group. The levels of serum nesfatin-1 and glucocorticoid in maternal separation group were statistically higher than those in the control group. The level of glucocorticoid was positively correlated with serum nesfatin-1 level. When the balloon pressure was set at 40, 60 and 80 mmHg, AWR score and EMG amplitude in the maternal separation group were significantly higher than those in the normal control group. AWR score and EMG amplitude in the maternal separation group were positively correlated with the level of serum nesfatin-1.
CONCLUSION: Rats subjected to maternal separation showed a higher AWR score and EMG amplitude, as well as elevated levels of serum nesfatin-1. Visceral hypersensitivity induced by neonatal maternal separation may be associated with elevated level of serum nesfatin-1.
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Moloney RD, Dinan TG, Cryan JF. Strain-dependent variations in visceral sensitivity: relationship to stress, anxiety and spinal glutamate transporter expression. GENES BRAIN AND BEHAVIOR 2015; 14:319-29. [PMID: 25851919 DOI: 10.1111/gbb.12216] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Responses to painful stimuli differ between populations, ethnic groups, sexes and even among individuals of a family. However, data regarding visceral pain are still lacking. Thus, we investigated differences in visceral nociception across inbred and outbred mouse strains using colorectal distension. Anxiety and depression-like behaviour were assessed using the open field and forced swim test as well as the corticosterone stress response. Possible mechanistic targets [excitatory amino acid transporter (EAAT-1), brain-derived neurotrophic factor (BDNF) and 5HT1A receptor] were also assessed using quantitative real-time polymerase chain reaction. Adult, male, inbred and outbred mouse strains were used in all assays (inbred strains; CBA/J Hsd, C3H/HeNHsd, BALB/c OlaHsd, C57 BL/6JOlaHsd, DBA/2J RccHsd, CAST/EiJ, SM/J, A/J OlaHsd, 129P2/OlaHsd, FVB/NHan Hsd and outbred strains: Swiss Webster, CD-1). mRNA expression levels of EAAT-1, BDNF and 5HT1A receptor (HTR1A) were quantified in the lumbosacral spinal cord, amygdala and hippocampus. A significant effect of strain was found in visceral sensitivity, anxiety and depressive-like behaviours. Strain differences were also seen in both baseline and stress-induced corticosterone levels. CBA/J mice consistently exhibited heightened visceral sensitivity, anxiety behaviour and depression-like behaviour which were associated with decreased spinal EAAT-1 and hippocampal BDNF and HTR1A. Our results show the CBA/J mouse strain as a novel mouse model to unravel the complex mechanisms of brain-gut axis disorders such as irritable bowel syndrome, in particular the underlying mechanisms of visceral hypersensitivity, for which there is great need. Furthermore, this study highlights the importance of genotype and the consequences for future development of transgenic strains in pain research.
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Affiliation(s)
- R D Moloney
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, Biosciences Institute, Ireland; Department of Psychiatry, Ireland
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Stephens RL. Glutamate transporter activators as anti-nociceptive agents. Eurasian J Med 2015; 43:182-5. [PMID: 25610189 DOI: 10.5152/eajm.2011.39] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2011] [Accepted: 11/23/2011] [Indexed: 12/21/2022] Open
Abstract
The effective management of chronic pain remains enigmatic. There is a paucity of effective mechanistically-based approaches employed. Chronic visceral pain is a particularly difficult subcategory to manage. Glutamate is the most predominant excitatory neurotransmitter and mediates many aspects of sensory function including acute and chronic pain. There is a growing literature describing the efficacy of physiologically dominant glutamate transporter GLT-1 up-regulation in attenuating chronic visceral and somatic nociception. Since glutamate is the major excitatory neurotransmitter released in the first central synapse of the pain-transmitting afferent neurons, augmentation of GLT-1 activity, which reduces extracellular levels of glutamate, may be an important target for pain management strategies. This review summarizes studies in our laboratory and others which highlight findings that GLT-1 up-regulation by transgenic, pharmacologic and viral transfection approaches attenuate a host of nociceptive responses emanating from visceral or somatic sources in animal models. The study also outlines the future work that will be required to ascertain the translational potential of this approach.
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Affiliation(s)
- Robert L Stephens
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio, USA
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46
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Moloney RD, O'Mahony SM, Dinan TG, Cryan JF. Stress-induced visceral pain: toward animal models of irritable-bowel syndrome and associated comorbidities. Front Psychiatry 2015; 6:15. [PMID: 25762939 PMCID: PMC4329736 DOI: 10.3389/fpsyt.2015.00015] [Citation(s) in RCA: 102] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Accepted: 01/28/2015] [Indexed: 12/12/2022] Open
Abstract
Visceral pain is a global term used to describe pain originating from the internal organs, which is distinct from somatic pain. It is a hallmark of functional gastrointestinal disorders such as irritable-bowel syndrome (IBS). Currently, the treatment strategies targeting visceral pain are unsatisfactory, with development of novel therapeutics hindered by a lack of detailed knowledge of the underlying mechanisms. Stress has long been implicated in the pathophysiology of visceral pain in both preclinical and clinical studies. Here, we discuss the complex etiology of visceral pain reviewing our current understanding in the context of the role of stress, gender, gut microbiota alterations, and immune functioning. Furthermore, we review the role of glutamate, GABA, and epigenetic mechanisms as possible therapeutic strategies for the treatment of visceral pain for which there is an unmet medical need. Moreover, we discuss the most widely described rodent models used to model visceral pain in the preclinical setting. The theory behind, and application of, animal models is key for both the understanding of underlying mechanisms and design of future therapeutic interventions. Taken together, it is apparent that stress-induced visceral pain and its psychiatric comorbidities, as typified by IBS, has a multifaceted etiology. Moreover, treatment strategies still lag far behind when compared to other pain modalities. The development of novel, effective, and specific therapeutics for the treatment of visceral pain has never been more pertinent.
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Affiliation(s)
- Rachel D Moloney
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, Biosciences Institute, University College Cork , Cork , Ireland
| | - Siobhain M O'Mahony
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, Biosciences Institute, University College Cork , Cork , Ireland ; Department of Anatomy and Neuroscience, University College Cork , Cork , Ireland
| | - Timothy G Dinan
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, Biosciences Institute, University College Cork , Cork , Ireland ; Department of Psychiatry, University College Cork , Cork , Ireland
| | - John F Cryan
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, Biosciences Institute, University College Cork , Cork , Ireland ; Department of Anatomy and Neuroscience, University College Cork , Cork , Ireland
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Prusator DK, Greenwood-Van Meerveld B. Gender specific effects of neonatal limited nesting on viscerosomatic sensitivity and anxiety-like behavior in adult rats. Neurogastroenterol Motil 2015; 27:72-81. [PMID: 25394875 DOI: 10.1111/nmo.12472] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Accepted: 10/21/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND Evidence exists to suggest that early life stress (ELS), such as neglect or abuse has profound effects on the developing brain. The current study tests the hypothesis that ELS in the form of neonatal limited nesting (LN) may serve as a predisposing factor for the development of altered nociceptive processing and comorbid increases in anxiety-like behavior in adulthood. METHODS Both male and female neonatal Sprague-Dawley rats were subjected to LN from postnatal day (PND) 2-9, while a control group was exposed to standard cage bedding. In adulthood, visceral sensitivity was assessed by quantifying a visceromotor behavioral response to graded isobaric pressures of colorectal distension. Hindpaw withdrawal thresholds in response to von Frey filaments were used to measure somatic sensitivity. Anxiety-like behavior was assessed in adult life using both the elevated plus maze and open field assay. KEY RESULTS Early life stress in the form of neonatal LN induced visceral and somatic hypersensitivity in adult male rats and augmented anxiety-like behavior. However, in adult cycling females, neonatal LN did not alter nociceptive processing or lead to changes in the levels of anxiety-like behavior. CONCLUSIONS & INFERENCES Our findings suggest that in male rats the LN model is a novel tool to investigate the long-term consequences of adverse early life experience on adult health.
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Affiliation(s)
- D K Prusator
- Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
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48
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Gegelashvili G, Bjerrum OJ. High-affinity glutamate transporters in chronic pain: an emerging therapeutic target. J Neurochem 2014; 131:712-30. [DOI: 10.1111/jnc.12957] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Revised: 09/18/2014] [Accepted: 09/25/2014] [Indexed: 01/13/2023]
Affiliation(s)
- Georgi Gegelashvili
- Department of Drug Design and Pharmacology; Faculty of Health and Medical Sciences; University of Copenhagen; Copenhagen Denmark
- Institute of Chemical Biology; Ilia State University; Tbilisi Georgia
| | - Ole J. Bjerrum
- Department of Drug Design and Pharmacology; Faculty of Health and Medical Sciences; University of Copenhagen; Copenhagen Denmark
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Schwaller F, Fitzgerald M. The consequences of pain in early life: injury-induced plasticity in developing pain pathways. Eur J Neurosci 2014; 39:344-52. [PMID: 24494675 PMCID: PMC4264936 DOI: 10.1111/ejn.12414] [Citation(s) in RCA: 183] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Revised: 10/04/2013] [Accepted: 10/07/2013] [Indexed: 12/14/2022]
Abstract
Pain in infancy influences pain reactivity in later life, but how and why this occurs is poorly understood. Here we review the evidence for developmental plasticity of nociceptive pathways in animal models and discuss the peripheral and central mechanisms that underlie this plasticity. Adults who have experienced neonatal injury display increased pain and injury-induced hyperalgesia in the affected region but mild injury can also induce widespread baseline hyposensitivity across the rest of the body surface, suggesting the involvement of several underlying mechanisms, depending upon the type of early life experience. Peripheral nerve sprouting and dorsal horn central sensitization, disinhibition and neuroimmune priming are discussed in relation to the increased pain and hyperalgesia, while altered descending pain control systems driven, in part, by changes in the stress/HPA axis are discussed in relation to the widespread hypoalgesia. Finally, it is proposed that the endocannabinoid system deserves further attention in the search for mechanisms underlying injury-induced changes in pain processing in infants and children.
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Affiliation(s)
- Fred Schwaller
- Department of Neuroscience, Physiology & Pharmacology, University College London, London, UK
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Mishra SP, Shukla SK, Pandey BL. A preliminary evaluation of comparative effectiveness of riluzole in therapeutic regimen for irritable bowel syndrome. Asian Pac J Trop Biomed 2014; 4:S335-40. [PMID: 25183107 DOI: 10.12980/apjtb.4.2014c205] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2014] [Accepted: 02/22/2014] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE To develop agents that are specifically effective in controlling the key disturbance of visceral hyperalgesia besides abating of associated multiple symptoms, and evaluate comparative effectiveness for IBS symptom relief for standard regimen (antispasmodic and probiotic) and add-on amitriptyine or riluzole regimens following two weeks administration. METHODS 108 patients with visceral hypersensitivity accompanying IBS, divided into three groups were studied. First group received standard treatment (mebeverine 200 mg twice daily and probiotic 200 mg twice daily). Second group received add-on amitriptyline 25 mg before bedtime, while the third group got add-on riluzole 50 mg twice daily. Overall gastrointestinal symptom rating scale improving symptoms and hospital anxiety depression scale improving associated psychological morbidity were employed as measures at induction and at two-week follow-up period. Individual symptom scores were also examined to define the outcome profiles. RESULTS Riluzole regimen resulted in significant reduction of overall gastrointestinal symptom rating scale score, not the other two regimens. Pain relief was seen with both riluzole and amitriptyline regimens significantly superior to standard treatment regimen, but riluzole effect appeared specific and independent anxiolytic effect. Amitriptyline caused relief in diarrhea and did not benefit in constipation point to non-specific remedial role in IBS. CONCLUSIONS Riluzole specifically relieves visceral hypersensitivity and is proved to be superior to current treatments in IBS patients. It appears a lead remedy based on glutamate transporter mechanisms in visceral hypersensititvity.
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Affiliation(s)
- Surya Prakash Mishra
- Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Sunit Kumar Shukla
- Department of Gastroenterology, Institute of Medical Sciences and Sir Sunderlal Hospital, Banaras Hindu University, Varanasi, India
| | - Bajrang Lal Pandey
- Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
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