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Barroso J, Branco P, Apkarian AV. The causal role of brain circuits in osteoarthritis pain. Nat Rev Rheumatol 2025; 21:261-274. [PMID: 40164779 DOI: 10.1038/s41584-025-01234-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/26/2025] [Indexed: 04/02/2025]
Abstract
Osteoarthritis (OA) is a leading cause of chronic pain worldwide, resulting in substantial disability and placing a substantial burden on patients and society. The hallmark symptom of OA is joint pain. Despite extensive research, new treatments for OA pain remain limited, partly owing to a lack of understanding of underlying pain mechanisms. For a long time, OA pain was seen as a reflection of nociceptive activity at the joint level, and the brain has been viewed as a passive recipient of such information. In this Review, we challenge these concepts and discuss how, over time, the activation of peripheral nociceptors leads to adaptations in the brain that dictate the properties and experience of OA pain. These adaptations are further influenced by the inherent properties of the brain. We review general concepts that distinguish pain from nociception, present evidence on the incongruity between joint injury and experience of OA pain, and review brain circuits that are crucial in the perception of OA pain. Finally, we propose a model that integrates nociception, spinal-cord mechanisms, and central nervous system dynamics, each contributing uniquely to pain perception. This framework has the potential to inform the development of personalized treatment strategies.
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Affiliation(s)
- Joana Barroso
- Department of Anaesthesiology and Center for Translational Pain Research, Feinberg School of Medicine, Northwestern University, Evanston, IL, USA
- Department of Physical Medicine and Rehabilitation, Feinberg School of Medicine, Northwestern University, Evanston, IL, USA
| | - Paulo Branco
- Department of Anaesthesiology and Center for Translational Pain Research, Feinberg School of Medicine, Northwestern University, Evanston, IL, USA.
| | - A Vania Apkarian
- Department of Anaesthesiology and Center for Translational Pain Research, Feinberg School of Medicine, Northwestern University, Evanston, IL, USA.
- Department of Physical Medicine and Rehabilitation, Feinberg School of Medicine, Northwestern University, Evanston, IL, USA.
- Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Evanston, IL, USA.
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2
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Gousset S, Cappe M, Lenoir C, Steyaert A, Lavand'homme P, Mouraux A, Lacroix V, van den Broeke EN. Preoperative susceptibility to developing secondary hyperalgesia is associated with post-thoracotomy pain at 2 months. Eur J Pain 2025; 29:e4768. [PMID: 39651902 PMCID: PMC11627004 DOI: 10.1002/ejp.4768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 11/23/2024] [Accepted: 11/28/2024] [Indexed: 12/12/2024]
Abstract
BACKGROUND Identifying the subset of patients at risk for developing persistent pain after surgery is clinically important as they could benefit from targeted prevention measures. In this prospective study, we investigated if the preoperative assessment of the individual susceptibility to developing experimentally induced secondary hyperalgesia is associated with post-thoracotomy pain at 2 months. METHODS Forty-one patients scheduled to undergo a posterolateral thoracotomy were recruited before surgery and followed prospectively for 2 months. The day before surgery, we experimentally induced secondary hyperalgesia at one of the two forearms and measured the change of perception to mechanical pinprick stimuli and the area of hyperalgesia. On postoperative Day 4, Day 15 and at the 2-month follow-up, patients were asked about their pain intensity at rest and during coughing and the area of secondary hyperalgesia around the scar as well as the change in perception to mechanical pinprick stimuli was measured. RESULTS Of the 41 patients that were recruited only 20 could be analysed. Forty per cent reported pain at the 2-month follow-up. All of them reported cough-evoked pain and 10 per cent also reported pain at rest. A binary logistic regression model with both the magnitude and extent of experimentally induced secondary hyperalgesia was statistically significant (chi-squared = 12.439, p = 0.002, McFadden R2 = 0.462) and showed excellent discriminative power (AUC = 0.938) for the presence or absence of cough-evoked pain at the 2 month follow-up. CONCLUSION Our findings indicate that the individual susceptibility to developing experimentally induced secondary hyperalgesia preoperatively may identify patients who are potentially vulnerable to develop persistent post-thoracotomy pain. SIGNIFICANCE Our data suggests that preoperatively assessed experimentally induced secondary hyperalgesia displays excellent discriminative power for the presence or absence of cough-evoked pain 2 months after thoracotomy.
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Affiliation(s)
- Solenn Gousset
- Institute of Neuroscience (IoNS)UCLouvainBrusselsBelgium
| | - Maximilien Cappe
- Institute for Experimental and Clinical Research (IREC)UCLouvainBrusselsBelgium
- Department of Anesthesiology, Cliniques Universitaires Saint LucUCLouvainBrusselsBelgium
- Department of Cardiovascular and Thoracic Surgery, Cliniques Universitaires Saint‐LucUCLouvainBrusselsBelgium
| | - Cedric Lenoir
- Institute of Neuroscience (IoNS)UCLouvainBrusselsBelgium
| | - Arnaud Steyaert
- Institute of Neuroscience (IoNS)UCLouvainBrusselsBelgium
- Institute for Experimental and Clinical Research (IREC)UCLouvainBrusselsBelgium
| | - Patricia Lavand'homme
- Institute of Neuroscience (IoNS)UCLouvainBrusselsBelgium
- Institute for Experimental and Clinical Research (IREC)UCLouvainBrusselsBelgium
| | - André Mouraux
- Institute of Neuroscience (IoNS)UCLouvainBrusselsBelgium
| | - Valérie Lacroix
- Institute for Experimental and Clinical Research (IREC)UCLouvainBrusselsBelgium
- Department of Cardiovascular and Thoracic Surgery, Cliniques Universitaires Saint‐LucUCLouvainBrusselsBelgium
| | - Emanuel N. van den Broeke
- Institute of Neuroscience (IoNS)UCLouvainBrusselsBelgium
- Health Psychology, Faculty of Psychology and Educational SciencesKU LeuvenLeuvenBelgium
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Plumb AN, Lesnak JB, Rasmussen L, Sluka KA. Female specific interactions of serotonin and testosterone in the rostral ventromedial medulla after activity-induced muscle pain. THE JOURNAL OF PAIN 2025; 26:104723. [PMID: 39522853 DOI: 10.1016/j.jpain.2024.104723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 10/03/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024]
Abstract
Classical preclinical studies show that serotonin (5-HT) injected into the rostral ventromedial medulla (RVM) produces analgesia that is blocked by 5-HT2 receptor antagonists. One key modulator of 5-HT activity is the serotonin transporter (SERT) which reduces serotonergic signaling through reuptake into the presynaptic terminal. In the activity-induced muscle pain model, females show widespread pain and increased SERT expression in the RVM whereas males show localized pain and no changes in SERT expression. Since prior studies show testosterone protects from the development of widespread pain, and females have widespread pain in the activity-induced pain model, we hypothesized that testosterone modulates serotonin signaling to enhance analgesia in female mice with widespread pain. We showed that testosterone reduced the enhanced SERT protein expression and increased 5-HT2A receptor mRNA expression in the RVM normally observed in the activity-induced pain model in females, but not males. Inhibition of SERT in the RVM was analgesic in both female and male mice; this analgesia was blocked by co-administration of 5-HT2A antagonist. Next, using in situ hybridization, we demonstrated co-expression of SERT, 5-HT2A receptor, and androgen receptor mRNA in cells within the RVM in female mice. Lastly, activation of androgen receptors using dihydrotestosterone reduced hyperalgesia in female mice. These data therefore show for the first time expression of androgen receptors in the RVM in female mice, that activation of androgen receptors reduces nociceptive behaviors, and endogenous testosterone modulates SERT and 5-HT2 receptor expression. Thus, we show a sex-specific role for how testosterone modulates analgesia in mice. PERSPECTIVE: This article presents novel mechanisms testosterone's protection against muscle pain in female mice showing modulation of the serotonin system in the rostral ventromedial medulla. Understanding the relationship between testosterone and serotonin could lead to better treatment of individuals with muscle pain.
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Affiliation(s)
- Ashley N Plumb
- Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, IA 52242, USA
| | - Joseph B Lesnak
- Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, IA 52242, USA
| | - Lynn Rasmussen
- Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, IA 52242, USA
| | - Kathleen A Sluka
- Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, IA 52242, USA; Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, IA 52242, USA.
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4
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Irvine KA, Shi XY, Ferguson AR, Clark JD. Designer Receptor Exclusively Activated by Designer Drug (DREADD)-Mediated Activation of the Periaqueductal Gray Restores Nociceptive Descending Inhibition After Traumatic Brain Injury in Rats. J Neurotrauma 2024; 41:e1761-e1779. [PMID: 38588130 PMCID: PMC11386998 DOI: 10.1089/neu.2024.0031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/10/2024] Open
Abstract
Traumatic brain injury (TBI) patients frequently experience chronic pain that can enhance their suffering and significantly impair rehabilitative efforts. Clinical studies suggest that damage to the periaqueductal gray matter (PAG) following TBI, a principal center involved in endogenous pain control, may underlie the development of chronic pain. We hypothesized that TBI would diminish the usual pain control functions of the PAG, but that directly stimulating this center using a chemogenetic approach would restore descending pain modulation. We used a well-characterized lateral fluid percussion model (1.3 ± 0.1 atm) of TBI in male rats (n = 271) and measured hindpaw mechanical nociceptive withdrawal thresholds using von Frey filaments. To investigate the role of the PAG in pain both before and after TBI, we activated the neurons of the PAG using a Designer Receptor Exclusively Activated by Designer Drug (DREADD) viral construct. Immunohistochemical analysis of brain tissue was used to assess the location and confirm the appropriate expression of the viral constructs in the PAG. Activation of the PAG DREADD using clozapine N-oxide (CNO) caused hindpaw analgesia that could be blocked using opioid receptor antagonist, naloxone, in uninjured but not TBI rats. Due to the importance of descending serotonergic signaling in modulating nociception, we ablated spinal serotonin signaling using 5,7-DHT. This treatment strongly reduced CNO-mediated anti-nociceptive effects in TBI but not uninjured rats. To define the serotonergic receptor(s) required for the CNO-stimulated effects in TBI rats, we administered 5-HT7 (SB-269970) and 5-HT1A (WAY-100635) receptor antagonists but observed no effects. The selective 5-HT2A receptor antagonist ketanserin, however, blocked CNO's effects in the DREADD expressing TBI but not DREADD expressing sham TBI animals. Blockade of alpha-1 adrenergic receptors with prazosin also had no effect after TBI. Descending pain control originating in the PAG is mediated through opioid receptors in uninjured rats. TBI, however, fundamentally alters the descending nociceptive control circuitry such that serotonergic influences predominate, and those are mediated by the 5-HT2A receptor. These results provide further evidence that the PAG is a key target for anti-nociception after TBI.
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Affiliation(s)
- Karen-Amanda Irvine
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California, USA
- Anesthesiology Service Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA
| | - Xiao-You Shi
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California, USA
- Anesthesiology Service Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA
| | - Adam R Ferguson
- Brain and Spinal Injury Center, Department of Neurosurgery, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California, USA
- San Francisco Veterans Affairs Healthcare System, San Francisco, California, USA
| | - J David Clark
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California, USA
- Anesthesiology Service Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA
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Dos Santos MA, Lemos AL, Machado MS, Lazaro LDOC, Paz MM, de Andrade AGP, Carpes FP. Effects of triceps surae exercise-induced delayed onset muscle soreness on control of body stability in different postures. J Electromyogr Kinesiol 2024; 76:102882. [PMID: 38599050 DOI: 10.1016/j.jelekin.2024.102882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 03/12/2024] [Accepted: 03/30/2024] [Indexed: 04/12/2024] Open
Abstract
This research aimed to determine whether triceps surae delayed onset muscle soreness (DOMS) affects stability while performing different postural control tasks requiring upright and landing stabilization. Twenty-four participants who self-reported as healthy were recruited. Pre and 48 h after a protocol to induce DOMS in the triceps surae, participants were evaluated for DOMS perception, pressure pain threshold, and postural control (assessed by the center of pressure, CoP) during different standing and landing stabilization tasks. We found higher DOMS perception and lower pressure pain threshold 48 h after the exercise. Mediolateral CoP displacement was more sensitive to DOMS across different postural tasks, but no effects were found for bilateral standing. The landing time to stabilization elicited high individual variability in the presence of DOMS. Effects of DOMS in the performance of less challenging tasks, such as bipedal standing, were not found. We conclude that DOMS in the triceps surae impairs mediolateral postural control during challenging tasks such as unilateral standing and body forward lean. It highlights the need for caution and individualized approaches when incorporating movements requiring frontal plane control in training and rehabilitation sessions under the presence of DOMS.
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Affiliation(s)
- Milena A Dos Santos
- Applied Neuromechanics Research Group, Federal University of Pampa, Uruguaiana, RS, Brazil
| | - Andressa L Lemos
- Applied Neuromechanics Research Group, Federal University of Pampa, Uruguaiana, RS, Brazil
| | - Mathias S Machado
- Applied Neuromechanics Research Group, Federal University of Pampa, Uruguaiana, RS, Brazil
| | - Laura de O C Lazaro
- Applied Neuromechanics Research Group, Federal University of Pampa, Uruguaiana, RS, Brazil
| | - Marieli M Paz
- Applied Neuromechanics Research Group, Federal University of Pampa, Uruguaiana, RS, Brazil
| | | | - Felipe P Carpes
- Applied Neuromechanics Research Group, Federal University of Pampa, Uruguaiana, RS, Brazil.
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Ye Y, Yan X, Wang L, Xu J, Li T. Transcranial direct current stimulation attenuates chronic pain in knee osteoarthritis by modulating BDNF/TrkB signaling in the descending pain modulation system. Neurosci Lett 2023; 810:137320. [PMID: 37295640 DOI: 10.1016/j.neulet.2023.137320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/15/2023] [Accepted: 06/05/2023] [Indexed: 06/12/2023]
Abstract
Knee osteoarthritis (KOA) is the most common cause of chronic pain, but its pain mechanisms are complex and may be closely related to the descending pain modulation system. Transcranial direct current stimulation (tDCS) is used for relieving pain, but its analgesic mechanisms are still being explored. The purpose of this study was to investigate the role of BDNF/TrkB signaling in chronic pain in KOA and to investigate whether this signaling is related to the analgesic effect of tDCS. Rats were injected with monosodium iodoacetate (MIA) into the left knee joint to establish a chronic pain model and then received 20 min of tDCS for 8 days. Rats were respectively administered the TrkB inhibitor ANA-12 after MIA modeling and exogenous BDNF after tDCS treatment. Behaviors testing was assessed by hot plate and von Frey hairs using the up-down method. In addition, the expression levels of BDNF and TrkB on the periaqueductal gray (PAG)-the rostral ventromedial medulla (RVM)-the spinal dorsal horn (SDH) axis were detected by Western blot and Immunohistochemistry staining. Behavioral results show that tDCS treatment and ANA-12 injection reversed MIA-induced allodynia while reducing BDNF and TrkB expression levels. Furthermore, injection of exogenous BDNF reversed the therapeutic effect of tDCS on pain. These results indicate that upregulation of the BDNF/TrkB signaling in the descending pain modulation system may play an important role in KOA-induced chronic pain in rats, and tDCS may reduce KOA-induced chronic pain by inhibiting the BDNF/TrkB signaling in the descending pain modulation system.
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Affiliation(s)
- Yinshuang Ye
- Department of Rehabilitation Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Xiao Yan
- Department of Rehabilitation Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Lin Wang
- Department of Rehabilitation Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Jiawei Xu
- Department of Rehabilitation Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Tieshan Li
- Department of Rehabilitation Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China.
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7
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Alotaibi G, Khan A, Ronan PJ, Lutfy K, Rahman S. Glial Glutamate Transporter Modulation Prevents Development of Complete Freund's Adjuvant-Induced Hyperalgesia and Allodynia in Mice. Brain Sci 2023; 13:807. [PMID: 37239279 PMCID: PMC10216248 DOI: 10.3390/brainsci13050807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 05/12/2023] [Accepted: 05/13/2023] [Indexed: 05/28/2023] Open
Abstract
Glial glutamate transporter (GLT-1) modulation in the hippocampus and anterior cingulate cortex (ACC) is critically involved in nociceptive pain. The objective of the study was to investigate the effects of 3-[[(2-methylphenyl) methyl] thio]-6-(2-pyridinyl)-pyridazine (LDN-212320), a GLT-1 activator, against microglial activation induced by complete Freund's adjuvant (CFA) in a mouse model of inflammatory pain. Furthermore, the effects of LDN-212320 on the protein expression of glial markers, such as ionized calcium-binding adaptor molecule 1 (Iba1), cluster of differentiation molecule 11b (CD11b), mitogen-activated protein kinases (p38), astroglial GLT-1, and connexin 43 (CX43), were measured in the hippocampus and ACC following CFA injection using the Western blot analysis and immunofluorescence assay. The effects of LDN-212320 on the pro-inflammatory cytokine interleukin-1β (IL-1β) in the hippocampus and ACC were also assessed using an enzyme-linked immunosorbent assay. Pretreatment with LDN-212320 (20 mg/kg) significantly reduced the CFA-induced tactile allodynia and thermal hyperalgesia. The anti-hyperalgesic and anti-allodynic effects of LDN-212320 were reversed by the GLT-1 antagonist DHK (10 mg/kg). Pretreatment with LDN-212320 significantly reduced CFA-induced microglial Iba1, CD11b, and p38 expression in the hippocampus and ACC. LDN-212320 markedly modulated astroglial GLT-1, CX43, and, IL-1β expression in the hippocampus and ACC. Overall, these results suggest that LDN-212320 prevents CFA-induced allodynia and hyperalgesia by upregulating astroglial GLT-1 and CX43 expression and decreasing microglial activation in the hippocampus and ACC. Therefore, LDN-212320 could be developed as a novel therapeutic drug candidate for chronic inflammatory pain.
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Affiliation(s)
- Ghallab Alotaibi
- Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA
| | - Amna Khan
- Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA
| | - Patrick J. Ronan
- Research Service, Sioux Falls VA Healthcare System, Sioux Falls, SD 57105, USA
- Department of Psychiatry and Basic Biomedical Sciences, University of South Dakota Sanford School of Medicine, Sioux Falls, SD 57105, USA
| | - Kabirullah Lutfy
- College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Shafiqur Rahman
- Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA
- Research Service, Sioux Falls VA Healthcare System, Sioux Falls, SD 57105, USA
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Shukla D, Bhola ND, Bhola RD, Nimje AM. Efficacy of Preoperative Piroxicam, Diclofenac, Paracetamol With Tramadol and Placebo Tablets for Relief of Postoperative Pain After the Removal of Impacted Mandibular Third Molars: A Randomised Controlled Trial. Cureus 2022; 14:e26839. [PMID: 35974862 PMCID: PMC9375129 DOI: 10.7759/cureus.26839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/14/2022] [Indexed: 11/28/2022] Open
Abstract
Aim We aimed to analyze the influence of preoperative piroxicam, diclofenac, paracetamol, tramadol, and placebo tablets as measured in the time required for rescue analgesia for postoperative pain relief after the extraction of impacted mandibular third molar. Materials & methods Forty-four patients who needed extraction of impacted mandibular third molar were arbitrarily categorized into four groups namely, piroxicam, diclofenac, paracetamol with tramadol, and placebo. The test medicine was given one hour preoperatively before the surgical removal. The pain was assessed using visual analog scale (VAS) and verbal rating scale (VRS) scores preoperatively and at the third and 24th hours. The time required for escape analgesia was measured. Results The mean VAS and VRS scores showed significant differences across the groups after 24 hours. The mean score was lowest for the patients taking piroxicam (1.30+1.95) and highest for patients taking tramadol + paracetamol (4.50+2.59). As far as escape analgesia is concerned piroxicam group was by far superior. Conclusion The pain scores and the rescue analgesic requirement suggested that piroxicam analgesic significantly reduced pain; moreover, it is a safe as well as an efficacious substitute to the conventional non-steroidal anti-inflammatory drugs (NSAIDs) for mandibular third molar impactions.
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Irvine KA, Peters CM, Vazey EM, Ferguson AR, Clark JD. Activation of the Locus Coeruleus Mediated by Designer Receptor Exclusively Activated by Designer Drug Restores Descending Nociceptive Inhibition after Traumatic Brain Injury in Rats. J Neurotrauma 2022; 39:964-978. [PMID: 35412843 PMCID: PMC9467637 DOI: 10.1089/neu.2021.0485] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Disruption of endogenous pain control mechanisms including descending pain inhibition has been linked to several forms of pain including chronic pain after traumatic brain injury (TBI). The locus coeruleus (LC) is the principal noradrenergic (NA) nucleus participating in descending pain inhibition. We therefore hypothesized that selectively stimulating LC neurons would reduce nociception after TBI. All experiments used a well-characterized rat lateral fluid percussion model of TBI. NA neurons were stimulated by administering clozapine N-oxide (CNO) to rats selectively expressing a designer receptor exclusively activated by designer drug (DREADD) viral construct in their LC's. Mechanical nociceptive thresholds were measured using von Frey fibers. The efficacy of diffuse noxious inhibitory control (DNIC), a critical endogenous pain control mechanism, was assessed using the hindpaw administration of capsaicin. Immunohistochemical analyses demonstrated the selective expression of the DREADD construct in LC neurons after stereotactic injection. During the 1st week after TBI, when rats demonstrated hindlimb (HL) nociceptive sensitization, CNO administration provided transient anti-allodynia in DREADD-expressing rats but not in rats injected with control virus. Seven weeks after TBI we observed a complete loss of DNIC in response to capsaicin. However, CNO administration largely restored DNIC in TBI DREADD-expressing rats but not those injected with control virus. Unexpectedly, the effects of LC activation in the DREADD-expressing rats were blocked by the α-1 adrenergic receptor antagonist prazosin, but not the α-2 adrenergic receptor antagonist atipamezole. These results suggest that directly stimulating the LC after TBI can reduce both early and late manifestations of dysfunctional endogenous pain regulation. Clinical approaches to activating descending pain circuits may reduce suffering in those with pain after TBI.
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Affiliation(s)
- Karen-Amanda Irvine
- Department of Anesthesiology, Perioperative and Pain Medicine; Stanford University, School of Medicine, Stanford, California, USA.,Anesthesiology Service; Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA.,Address correspondence to: Karen-Amanda Irvine, PhD, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, School of Medicine, Stanford, CA 94305, USA
| | - Christopher M. Peters
- Department of Anesthesiology, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, USA
| | - Elena M. Vazey
- Department of Biology, University of Massachusetts Amherst, Amherst Massachusetts, USA
| | - Adam R. Ferguson
- University of California San Francisco, Brain and Spinal Injury Center, Department of Neurosurgery, San Francisco, California, USA
| | - J. David Clark
- Department of Anesthesiology, Perioperative and Pain Medicine; Stanford University, School of Medicine, Stanford, California, USA.,Anesthesiology Service; Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA
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10
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Bedwell GJ, Louw C, Parker R, van den Broeke E, Vlaeyen JW, Moseley GL, Madden VJ. The influence of a manipulation of threat on experimentally-induced secondary hyperalgesia. PeerJ 2022; 10:e13512. [PMID: 35757170 PMCID: PMC9220919 DOI: 10.7717/peerj.13512] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 05/07/2022] [Indexed: 01/17/2023] Open
Abstract
Pain is thought to be influenced by the threat value of the particular context in which it occurs. However, the mechanisms by which a threat achieves this influence on pain are unclear. Here, we explore how threat influences experimentally-induced secondary hyperalgesia, which is thought to be a manifestation of central sensitization. We developed an experimental study to investigate the effect of a manipulation of threat on experimentally-induced secondary hyperalgesia in 26 healthy human adults (16 identifying as female; 10 as male). We induced secondary hyperalgesia at both forearms using high-frequency electrical stimulation. Prior to the induction, we used a previously successful method to manipulate threat of tissue damage at one forearm (threat site). The effect of the threat manipulation was determined by comparing participant-rated anxiety, perceived threat, and pain during the experimental induction of secondary hyperalgesia, between the threat and control sites. We hypothesized that the threat site would show greater secondary hyperalgesia (primary outcome) and greater surface area (secondary outcome) of induced secondary hyperalgesia than the control site. Despite a thorough piloting procedure to test the threat manipulation, our data showed no main effect of site on pain, anxiety, or threat ratings during high-frequency electrical stimulation. In the light of no difference in threat between sites, the primary and secondary hypotheses cannot be tested. We discuss reasons why we were unable to replicate the efficacy of this established threat manipulation in our sample, including: (1) competition between threats, (2) generalization of learned threat value, (3) safety cues, (4) trust, and requirements for participant safety, (5) sampling bias, (6) sample-specific habituation to threat, and (7) implausibility of (sham) skin examination and report. Better strategies to manipulate threat are required for further research on the mechanisms by which threat influences pain.
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Affiliation(s)
- Gillian J. Bedwell
- Department of Health and Rehabilitation Sciences, University of Cape Town, Cape Town, Western Cape, South Africa,Pain Unit, Department of Anaesthesia and Perioperative Medicine, Neuroscience Institute, University of Cape Town, Cape Town, Western Cape, South Africa
| | - Caron Louw
- Pain Unit, Department of Anaesthesia and Perioperative Medicine, Neuroscience Institute, University of Cape Town, Cape Town, Western Cape, South Africa
| | - Romy Parker
- Pain Unit, Department of Anaesthesia and Perioperative Medicine, Neuroscience Institute, University of Cape Town, Cape Town, Western Cape, South Africa
| | - Emanuel van den Broeke
- Institute of Neuroscience, Division Cognitive and Systems, UC Louvain, Brussels, Belgium
| | - Johan W. Vlaeyen
- Research Group Health Psychology, KU Leuven, Leuven, Belgium,Experimental Health Psychology, University of Maastricht, Maastricht, Netherlands
| | | | - Victoria J. Madden
- Pain Unit, Department of Anaesthesia and Perioperative Medicine, Neuroscience Institute, University of Cape Town, Cape Town, Western Cape, South Africa,Research Group Health Psychology, KU Leuven, Leuven, Belgium,IIMPACT in Health, University of South Australia, Adelaide, Australia,Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, Cape Town, Western Cape, South Africa
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You HJ, Lei J, Pertovaara A. Thalamus: The 'promoter' of endogenous modulation of pain and potential therapeutic target in pathological pain. Neurosci Biobehav Rev 2022; 139:104745. [PMID: 35716873 DOI: 10.1016/j.neubiorev.2022.104745] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 06/11/2022] [Indexed: 11/25/2022]
Abstract
More recently, the thalamic mediodorsal (MD) and ventromedial (VM) nuclei have been revealed to be functioned as 'nociceptive discriminator' in discriminating noxious and innocuous peripheral afferents, and exhibits distinct different descending controls of nociception. Of particularly importance, the function of thalamic nuclei in engaging descending modulation of nociception is 'silent' or inactive during the physiological state as well as in condition exposed to insufficient noxious stimulation. Once initiation by sufficient noxious or innocuous C-afferents associated with temporal and spatial summation, the thalamic MD and VM nuclei exhibit salient, different effects: facilitation and inhibition, on noxious mechanically and heat evoked nociception, respectively. Based on series of experimental evidence, we here summarize a novel hypothesis involving thalamic MD and VM nuclei functioned as 'promoter' in initiating descending facilitation and inhibition of pain with specific spatiotemporal characteristics. We further hypothesize that clinical remedy in targeting thalamic VM nucleus by enhancing its activities in recruiting inhibition alone or decreasing thalamic MD nucleus induced facilitation may provide promising way in effectively control of pathological pain.
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Affiliation(s)
- Hao-Jun You
- Center for Translational Medicine Research on Sensory-Motor Diseases, Yan'an University, Yan'an 716000, PR China; Key Laboratory of Yan'an Sports Rehabilitation Medicine, Yan'an 716000, PR China.
| | - Jing Lei
- Center for Translational Medicine Research on Sensory-Motor Diseases, Yan'an University, Yan'an 716000, PR China; Key Laboratory of Yan'an Sports Rehabilitation Medicine, Yan'an 716000, PR China
| | - Antti Pertovaara
- Department of Physiology, Faculty of Medicine, University of Helsinki, POB 63, Helsinki 00014, Finland
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Methylene blue prevents osteoarthritis progression and relieves pain in rats via upregulation of Nrf2/PRDX1. Acta Pharmacol Sin 2022; 43:417-428. [PMID: 33833406 DOI: 10.1038/s41401-021-00646-z] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Accepted: 02/04/2021] [Indexed: 02/06/2023]
Abstract
Oxidative stress-related cartilage degeneration, synovitis, and joint pain play vital roles in the progress of osteoarthritis (OA). Anti-oxidative stress agents not only prevent structural damage progression but also relieve OA-related pain. In this study, we investigated the therapeutic effect of methylene blue (MB), a classical and important anti-oxidant with strong neural affinity. Experimental OA was established in rats by radial transection of medial collateral ligament and medial meniscus (MCLT + MMT) of the right knee joint. The OA rats received intra-articular injection of MB (1 mg/kg) every week starting one week after surgery. We showed that MB administration exerted significant cartilage protection, synovitis inhibition as well as pain relief in OA rats. In human chondrocytes and fibroblast-like synoviocytes, MB significantly attenuated tert-butyl hydroperoxide (TBHP)-induced inflammatory response and oxidative stress. We demonstrated that these effects of MB resulted from dual targets of important antioxidant enzymes, Nrf2 and PRDX1, which also mutually reinforcing and participated in an interaction. Furthermore, we found that calcitonin gene-related peptide (CGRP), a neural inflammatory mediator, was accumulated around the vessel in synovium and subchondral bone in OA rats and in TBHP-treated primary cortical neurons; MB administration significantly inhibited CGRP expression through upregulation of Nrf2 and PRDX1. Taken together, these results suggest that MB ameliorates oxidative stress via Nrf2/PRDX1 regulation to prevent progression and relieve pain of OA.
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13
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Louwies T, Meerveld BGV. Abdominal Pain. COMPREHENSIVE PHARMACOLOGY 2022:132-163. [DOI: 10.1016/b978-0-12-820472-6.00037-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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14
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Tamada M, Ohi Y, Kodama D, Miyazawa K, Goto S, Haji A. Modulation of excitatory synaptic transmissions by TRPV1 in the spinal trigeminal subnucleus caudalis neurons of neuropathic pain rats. Eur J Pharmacol 2021; 913:174625. [PMID: 34758353 DOI: 10.1016/j.ejphar.2021.174625] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 10/29/2021] [Accepted: 11/04/2021] [Indexed: 01/16/2023]
Abstract
The present study examined contribution of the transient receptor potential vanilloid 1 channel (TRPV1) to the chronic orofacial pain. Bilateral partial nerve ligation (PNL) of the mental nerve, a branch of trigeminal nerve, was performed to induce neuropathic pain. The withdrawal threshold in response to mechanical stimulation of the lower lip skin was substantially reduced after the surgery in the PNL rats while it remained unchanged in the sham rats. This reduction in the PNL rats was alleviated by pregabalin injected intraperitoneally (10 mg/kg) and intracisternally (10, 30, 100 μg). Furthermore, an intracisternal injection of AMG9810, an antagonist of TRPV1, (1.5, 5.0 μg) attenuated the reduction of withdrawal threshold. Spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs) were recorded from the spinal trigeminal subnucleus caudalis (Vc) neurons in the brainstem slice, which receive the orofacial nociceptive signals. In the PNL rats, superfusion of capsaicin (0.03, 0.1 μM) enhanced their frequency without effect on the amplitude and the highest concentration (0.3 μM) increased both the frequency and amplitude. In the sham rats, only 0.3 μM capsaicin increased their frequency. Thus, capsaicin-induced facilitation of sEPSCs and mEPSCs in the PNL rats was significantly stronger than that in the sham rats. AMG9810 (0.1 μM) attenuated the capsaicin's effect. Capsaicin was ineffective on the trigeminal tract-evoked EPSCs in the PNL and sham rats. These results suggest that the chronic orofacial pain in the PNL model results from facilitation of the spontaneous excitatory synaptic transmission in the Vc region through TRPV1 at least partly.
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Affiliation(s)
- Mayo Tamada
- Laboratory of Neuropharmacology, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, 464-8650, Japan; Department of Orthodontics, School of Dentistry, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, 464-8650, Japan.
| | - Yoshiaki Ohi
- Laboratory of Neuropharmacology, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, 464-8650, Japan.
| | - Daisuke Kodama
- Laboratory of Neuropharmacology, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, 464-8650, Japan.
| | - Ken Miyazawa
- Department of Orthodontics, School of Dentistry, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, 464-8650, Japan.
| | - Shigemi Goto
- Department of Orthodontics, School of Dentistry, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, 464-8650, Japan.
| | - Akira Haji
- Laboratory of Neuropharmacology, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, 464-8650, Japan.
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Mills EP, Keay KA, Henderson LA. Brainstem Pain-Modulation Circuitry and Its Plasticity in Neuropathic Pain: Insights From Human Brain Imaging Investigations. FRONTIERS IN PAIN RESEARCH 2021; 2:705345. [PMID: 35295481 PMCID: PMC8915745 DOI: 10.3389/fpain.2021.705345] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 06/23/2021] [Indexed: 11/17/2022] Open
Abstract
Acute pain serves as a protective mechanism that alerts us to potential tissue damage and drives a behavioural response that removes us from danger. The neural circuitry critical for mounting this behavioural response is situated within the brainstem and is also crucial for producing analgesic and hyperalgesic responses. In particular, the periaqueductal grey, rostral ventromedial medulla, locus coeruleus and subnucleus reticularis dorsalis are important structures that directly or indirectly modulate nociceptive transmission at the primary nociceptive synapse. Substantial evidence from experimental animal studies suggests that plasticity within this system contributes to the initiation and/or maintenance of chronic neuropathic pain, and may even predispose individuals to developing chronic pain. Indeed, overwhelming evidence indicates that plasticity within this circuitry favours pro-nociception at the primary synapse in neuropathic pain conditions, a process that ultimately contributes to a hyperalgesic state. Although experimental animal investigations have been crucial in our understanding of the anatomy and function of the brainstem pain-modulation circuitry, it is vital to understand this system in acute and chronic pain states in humans so that more effective treatments can be developed. Recent functional MRI studies have identified a key role of this system during various analgesic and hyperalgesic responses including placebo analgesia, offset analgesia, attentional analgesia, conditioned pain modulation, central sensitisation and temporal summation. Moreover, recent MRI investigations have begun to explore brainstem pain-modulation circuitry plasticity in chronic neuropathic pain conditions and have identified altered grey matter volumes and functioning throughout the circuitry. Considering the findings from animal investigations, it is likely that these changes reflect a shift towards pro-nociception that ultimately contributes to the maintenance of neuropathic pain. The purpose of this review is to provide an overview of the human brain imaging investigations that have improved our understanding of the pain-modulation system in acute pain states and in neuropathic conditions. Our interpretation of the findings from these studies is often guided by the existing body of experimental animal literature, in addition to evidence from psychophysical investigations. Overall, understanding the plasticity of this system in human neuropathic pain conditions alongside the existing experimental animal literature will ultimately improve treatment options.
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Chen F, Gao W, Hu J, Yang X, Chai X, Wang D. Preoperative angiotensin II type 2 receptor is a predictor for developing chronic post-surgical pain after total knee arthroplasty surgery. Life Sci 2021; 278:119654. [PMID: 34043993 DOI: 10.1016/j.lfs.2021.119654] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 05/07/2021] [Accepted: 05/19/2021] [Indexed: 10/21/2022]
Abstract
OBJECTIVE This study aimed to explore whether preoperative angiotensin II type 2 receptor (AT2R) level in knee osteoarthritis (OA) patients was an independent risk factor for chronic post-surgical pain (CPSP) after total knee arthroplasty (TKA). METHODS A total of 220 patients who had undergone unilateral TKA were enrolled from October 2019 to January 2020. Quantitative sensory testing (QST), PainDETECT questionnaires (PD-Q), the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC), the hospital anxiety and depression (HAD) and serum AT2R were collected preoperatively. The primary outcome was the incidence of CPSP, which was defined as the visual analogue scale (VAS) score ≥ 4 in the ipsilateral knee joint six months after operation. RESULTS The prevalence of CPSP was 13.6% (n = 30). Multiple logistic regression analysis showed that patients with higher AT2R level (OR: 1.007, 95% CI: 1.003-1.011) and PD-Q score (OR: 1.146, 95% CI: 1.008-1.298) before surgery had an increased risk of CPSP after surgery, and a combination of preoperative AT2R and PD-Q (Akaike information criterion: 147.2; area under receiver operating characteristic (ROC) curve: 0.890) was able to correctly classify 90.16% of patients into CPSP positive or negative groups. CONCLUSION Our findings suggest that patients with higher preoperative AT2R level are at increased risk of developing CPSP following TKA. AT2R may serve as a candidate predictor for phenotyping CPSP in OA patients.
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Affiliation(s)
- Fan Chen
- Department of Anesthesiology, Anhui Provincial Hospital, Anhui Medical University, Hefei, China; Department of Anesthesiology, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei, China
| | - Wei Gao
- Department of Anesthesiology, Anhui Provincial Hospital, Anhui Medical University, Hefei, China; Department of Anesthesiology, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei, China
| | - Jicheng Hu
- Department of Anesthesiology, Anhui Provincial Hospital, Anhui Medical University, Hefei, China; Department of Anesthesiology, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei, China
| | - Xinlu Yang
- Department of Anesthesiology, Anhui Provincial Hospital, Anhui Medical University, Hefei, China; Department of Anesthesiology, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei, China
| | - Xiaoqing Chai
- Department of Anesthesiology, Anhui Provincial Hospital, Anhui Medical University, Hefei, China; Department of Anesthesiology, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei, China.
| | - Di Wang
- Department of Anesthesiology, Anhui Provincial Hospital, Anhui Medical University, Hefei, China; Department of Anesthesiology, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei, China.
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17
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Abstract
Chronic widespread pain conditions are more prevalent in women than men, suggesting a role for gonadal hormones in the observed differences. Previously, we showed that female mice, compared to male, develop widespread, more severe, and longer-duration hyperalgesia in a model of activity-induced muscle pain. We hypothesized testosterone protects males from developing the female pain phenotype. We tested whether orchiectomy of males before induction of an activity-induced pain model produced a female phenotype and whether testosterone administration produced a male phenotype in females. Orchiectomy produced longer-lasting, more widespread hyperalgesia, similar to females. Administration of testosterone to females or orchiectomized males produced unilateral, shorter-lasting hyperalgesia. Prior studies show that the serotonin transporter (SERT) is increased in the nucleus raphe magnus (NRM) in models of chronic pain, and that blockade of SERT in the NRM reduces hyperalgesia. We examined potential sex differences in the distribution of SERT across brain sites involved in nociceptive processing using immunohistochemistry. A sex difference in SERT was found in the NRM in the activity-induced pain model; females had greater SERT immunoreactivity than males. This suggests that testosterone protects against development of widespread, long-lasting muscle pain and that alterations in SERT may underlie the sex differences.
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18
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Abstract
Neuropathic pain (NeP) can result from sources as varied as nerve compression, channelopathies, autoimmune disease, and incision. By identifying the neurobiological changes that underlie the pain state, it will be clinically possible to exploit mechanism-based therapeutics for maximum analgesic effect as diagnostic accuracy is optimized. Obtaining sufficient knowledge regarding the neuroadaptive alterations that occur in a particular NeP state will result in improved patient analgesia and a mechanism-based, as opposed to a disease-based, therapeutic approach to facilitate target identification. This will rely on comprehensive disease pathology insight; our knowledge is vastly improving due to continued forward and back translational preclinical and clinical research efforts. Here we discuss the clinical aspects of neuropathy and currently used drugs whose mechanisms of action are outlined alongside their clinical use. Finally, we consider sensory phenotypes, patient clusters, and predicting the efficacy of an analgesic for neuropathy.
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Affiliation(s)
- Kirsty Bannister
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE1 1UL, United Kingdom;
| | - Juliane Sachau
- Division of Neurological Pain Research and Therapy, Department of Neurology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Ralf Baron
- Division of Neurological Pain Research and Therapy, Department of Neurology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Anthony H Dickenson
- Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom
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19
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Irvine KA, Sahbaie P, Ferguson AR, Clark JD. Loss of diffuse noxious inhibitory control after traumatic brain injury in rats: A chronic issue. Exp Neurol 2020; 333:113428. [PMID: 32745472 PMCID: PMC11793995 DOI: 10.1016/j.expneurol.2020.113428] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 07/23/2020] [Accepted: 07/25/2020] [Indexed: 02/07/2023]
Abstract
Chronic pain is one of the most challenging and debilitating symptoms to manage after traumatic brain injury (TBI), yet the underlying mechanisms remain elusive. The disruption of normal endogenous pain control mechanisms has been linked to several forms of chronic pain and may play a role in pain after TBI. We hypothesized therefore that dysfunctional descending noradrenergic and serotonergic pain control circuits may contribute to the loss of diffuse noxious inhibitory control (DNIC), a critical endogenous pain control mechanism, weeks to months after TBI. For these studies, the rat lateral fluid percussion model of mild TBI was used along with a DNIC paradigm involving a capsaicin-conditioning stimulus. We observed sustained failure of the DNIC response up to 180-days post injury. We confirmed, that descending α2 adrenoceptor-mediated noradrenergic signaling was critical for endogenous pain inhibition in uninjured rats. However, augmenting descending noradrenergic signaling using reboxetine, a selective noradrenaline reuptake inhibitor, failed to restore DNIC after TBI. Furthermore, blocking serotonin-mediated descending signaling using selective spinal serotonergic fiber depletion with 5, 7-dihydroxytryptamine was also unsuccessful at restoring endogenous pain modulation after TBI. Unexpectedly, increasing descending serotonergic signaling using the selective serotonin reuptake inhibitor escitalopram and the serotonin-norepinephrine reuptake inhibitor duloxetine restored the DNIC response in TBI rats at both 49- and 180- days post injury. Consistent with these observations, spinal serotonergic fiber depletion with 5, 7-dihydroxytryptamine eliminated the effects of escitalopram. Intact α2 adrenoceptor signaling, however, was not required for the serotonin-mediated restoration of DNIC after TBI. These results suggest that TBI causes maladaptation of descending nociceptive signaling mechanisms and changes in the function of both adrenergic and serotonergic circuits. Such changes could predispose those with TBI to chronic pain.
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Affiliation(s)
- Karen-Amanda Irvine
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, School of Medicine, Stanford, CA 94305, USA; Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave (E4-220), Palo Alto, CA 94304, USA.
| | - Peyman Sahbaie
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, School of Medicine, Stanford, CA 94305, USA; Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave (E4-220), Palo Alto, CA 94304, USA
| | - Adam R Ferguson
- University of California San Francisco, Brain and Spinal Injury Center, Department Neurosurgery, 1001 Potrero Ave, San Francisco, CA 94110, USA
| | - J David Clark
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, School of Medicine, Stanford, CA 94305, USA; Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave (E4-220), Palo Alto, CA 94304, USA
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20
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Enhanced spinal neuronal responses as a mechanism for increased number and size of active acupoints in visceral hyperalgesia. Sci Rep 2020; 10:10312. [PMID: 32587303 PMCID: PMC7316812 DOI: 10.1038/s41598-020-67242-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 06/04/2020] [Indexed: 11/27/2022] Open
Abstract
Acupuncture has been used to treat a variety of illness and involves the insertion and manipulation of needles into specific points on the body (termed “acupoints”). It has been suggested that acupoints are not merely discrete, static points, but can be dynamically changed according to the pathological state of internal organs. We investigated in a rat model of mustard oil (MO)-induced visceral hyperalgesia whether the number and size of acupoints were modified according to the severity of the colonic pain, and whether the changes were associated with enhanced activity of the spinal dorsal horn. In MO-treated rats, acupoints showing neurogenic inflammation (termed “neurogenic spots” or Neuro-Sps) were found both bilaterally and unilaterally on the leg. The number and size of these acupoints increased along with increasing doses of MO. Electroacupuncture of the acupoints generated analgesic effects on MO-induced visceral hypersensitivity. The MO-treated rats showed an increase in c-Fos expression in spinal dorsal horn neurons and displayed increased evoked activity and a prolonged after-discharge in spinal wide dynamic response (WDR) neurons in response to colorectal distension. Increased number and size of neurogenic inflammatory acupoints following MO treatment were reduced by inhibiting AMPA and NMDA receptors in the spinal cord. Our findings suggest that acupoints demonstrate increased number and size along with severity of visceral pain, which may be associated with enhanced neuronal responses in spinal dorsal horn neurons.
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21
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Bumgarner JR, Walker WH, Liu JA, Walton JC, Nelson RJ. Dim Light at Night Exposure Induces Cold Hyperalgesia and Mechanical Allodynia in Male Mice. Neuroscience 2020; 434:111-119. [PMID: 32201267 PMCID: PMC7176554 DOI: 10.1016/j.neuroscience.2020.03.022] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 03/10/2020] [Accepted: 03/12/2020] [Indexed: 01/13/2023]
Abstract
The growing presence of artificial lighting across the globe presents a number of challenges to human and ecological health despite its societal benefits. Exposure to artificial light at night, a seemingly innocuous aspect of modern life, disrupts behavior and physiological functions. Specifically, light at night induces neuroinflammation, which is implicated in neuropathic and nociceptive pain states, including hyperalgesia and allodynia. Because of its influence on neuroinflammation, we investigated the effects of dim light at night exposure on pain responsiveness in male mice. In this study, mice exposed to four days of dim (5 lux) light at night exhibited cold hyperalgesia. Further, after 28 days of exposure, mice exhibited both cold hyperalgesia and mechanical allodynia. No heat/hot hyperalgesia was observed in this experiment. Altered nociception in mice exposed to dim light at night was concurrent with upregulated interleukin-6 and nerve growth factor mRNA expression in the medulla and elevated μ-opioid receptor mRNA expression in the periaqueductal gray region of the brain. The current results support the relationship between disrupted circadian rhythms and altered pain sensitivity. In summary, we observed that dim light at night induces cold hyperalgesia and mechanical allodynia, potentially through elevated neuroinflammation and dysregulation of the endogenous opioid system.
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Affiliation(s)
- Jacob R Bumgarner
- Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV 26506, USA.
| | - William H Walker
- Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV 26506, USA
| | - Jennifer A Liu
- Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV 26506, USA
| | - James C Walton
- Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV 26506, USA
| | - Randy J Nelson
- Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV 26506, USA
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22
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Zhang C, Xia C, Zhang X, Li W, Miao X, Zhou Q. Wrist-ankle acupuncture attenuates cancer-induced bone pain by regulating descending pain-modulating system in a rat model. Chin Med 2020; 15:13. [PMID: 32042305 PMCID: PMC7001307 DOI: 10.1186/s13020-020-0289-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 01/09/2020] [Indexed: 01/26/2023] Open
Abstract
Background Cancer-induced bone pain (CIBP) presents a multiple-mechanism of chronic pain involving both inflammatory and neuropathic pain, and its pathogenesis is closely related to endogenous descending system of pain control. However, the action mechanism underlying the effects of wrist–ankle acupuncture (WAA) versus electroacupuncture (EA) on CIBP remains unknown. Methods Thirty-two Wistar rats were divided into sham, CIBP, EA-treated and WAA-treated groups. CIBP was induced in rats of the latter three groups. Time courses of weight and mechanical hyperalgesia threshold (MHT) were evaluated. After 6 days of EA or WAA treatment, the expressions of 5-hydroxytryotamine type 3A receptor (5-HT3AR) and μ-opioid receptor (MOR) in rostral ventromedial medulla (RVM) and/or spinal cord, as well as the levels of 5-HT, β-endorphin, endomorphin-1 and endomorphin-2 in RVM and spinal cord, were detected. Results Injection of cancer cells caused decreased MHT, which was attenuated by EA or WAA (P < 0.05). WAA had a quicker analgesic effect than EA (P < 0.05). No significant difference of MOR in RVM was found among the four groups. EA or WAA counteracted the cancer-driven upregulation of 5-HT3AR and downregulation of MOR in spinal cord (P < 0.05), and upregulation of 5-HT and downregulation of endomorphin-1 in both RVM and spinal cord (P < 0.05). β-endorphin and endomorphin-2 in RVM and spinal cord decreased in CIBP group compared with sham group (P < 0.05), but EA or WAA showed no significant effect on them, although a tendency of increasing effect was observed. Conclusion WAA, similar to EA, alleviated mechanical hyperalgesia in CIBP rats by suppressing the expressions of 5-HT and 5-HT3AR, and increasing the expressions of MOR and endomorphin-1 in RVM-spinal cord pathway of the descending pain-modulating system. However, WAA produced a quicker analgesic effect than EA, the mechanisms of which need further investigation.
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Affiliation(s)
- Chunpeng Zhang
- School of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433 People's Republic of China
| | - Chen Xia
- School of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433 People's Republic of China
| | - Xiaowen Zhang
- School of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433 People's Republic of China
| | - Weimin Li
- 2Laboratory of Neuronal Network and Systems Biology, Shanghai Medical College, Fudan University, Shanghai, 200032 China
| | - Xuerong Miao
- Department of Anesthesiology, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road, Shanghai, 200433 People's Republic of China
| | - Qinghui Zhou
- School of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433 People's Republic of China
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Gonzalez-Cano R, Montilla-García Á, Perazzoli G, Torres JM, Cañizares FJ, Fernández-Segura E, Costigan M, Baeyens JM, Cobos EJ. Intracolonic Mustard Oil Induces Visceral Pain in Mice by TRPA1-Dependent and -Independent Mechanisms: Role of Tissue Injury and P2X Receptors. Front Pharmacol 2020; 11:613068. [PMID: 33551815 PMCID: PMC7859884 DOI: 10.3389/fphar.2020.613068] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 12/14/2020] [Indexed: 12/03/2022] Open
Abstract
Both TRPA1 and purinergic P2X receptors have been proposed as potential targets for the treatment of visceral pain. We found that the intracolonic administration of a low dose mustard oil (0.5%), a well-known TRPA1 agonist, produced nociceptive responses and abdominal wall referred mechanical hyperalgesia, without inducing apparent tissue damage. Both nociceptive responses and referred hyperalgesia were abolished by the ablation of TRPV1-expressing neurons (and the consequent ablation of TRPA1+ nociceptors) by resiniferatoxin (RTX) treatment, and by the TRPA1 antagonist AP18. However, a higher dose of mustard oil (2.5%) damaged the colonic epithelium and induced pERK activation in the spinal cord, and these processes were clearly independent of TRPV1-expressing neurons ablated by RTX. This higher dose of mustard oil induced nociceptive responses and referred mechanical hyperalgesia which were insensitive or only slightly sensitive to resiniferatoxin or AP18, but were markedly reduced by the P2X antagonist TNP-ATP, which is known to inhibit nociceptive actions induced by ATP released from injured tissues. In conclusion, whereas a low dose of intracolonic mustard oil induces visceral pain in a manner fully dependent on TRPA1 actions, when a high dose of this chemical irritant is used, visceral pain becomes mostly independent of TRPA1 activation but clearly enhanced by ATP purportedly released by the damaged colonic epithelium. Therefore, TRPA1 inhibition is not sufficient to substantially decrease visceral pain during tissue injury, whereas purinergic antagonism appears to be a more effective strategy.
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Affiliation(s)
- Rafael Gonzalez-Cano
- Department of Pharmacology, Faculty of Medicine, University of Granada, Granada, Spain
- Institute of Neuroscience, Biomedical Research Center, University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain
- *Correspondence: Enrique J. Cobos, ; Rafael González-Cano,
| | - Ángeles Montilla-García
- Department of Pharmacology, Faculty of Medicine, University of Granada, Granada, Spain
- Institute of Neuroscience, Biomedical Research Center, University of Granada, Granada, Spain
| | - Gloria Perazzoli
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, Spain
| | - Jesús M. Torres
- Institute of Neuroscience, Biomedical Research Center, University of Granada, Granada, Spain
- Department of Biochemistry, Molecular Biology and Immunology, Faculty of Medicine, University of Granada, Granada, Spain
| | - Francisco J. Cañizares
- Institute of Neuroscience, Biomedical Research Center, University of Granada, Granada, Spain
- Department of Histology, Faculty of Medicine, University of Granada, Granada, Spain
| | - Eduardo Fernández-Segura
- Institute of Neuroscience, Biomedical Research Center, University of Granada, Granada, Spain
- Department of Histology, Faculty of Medicine, University of Granada, Granada, Spain
| | - Michael Costigan
- Departments of Anesthesia and Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
| | - José M. Baeyens
- Department of Pharmacology, Faculty of Medicine, University of Granada, Granada, Spain
- Institute of Neuroscience, Biomedical Research Center, University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain
| | - Enrique J. Cobos
- Department of Pharmacology, Faculty of Medicine, University of Granada, Granada, Spain
- Institute of Neuroscience, Biomedical Research Center, University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain
- Teófilo Hernando Institute for Drug Discovery, Madrid, Spain
- *Correspondence: Enrique J. Cobos, ; Rafael González-Cano,
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24
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Enhanced descending pain facilitation in acute traumatic brain injury. Exp Neurol 2019; 320:112976. [PMID: 31185197 DOI: 10.1016/j.expneurol.2019.112976] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 05/25/2019] [Accepted: 06/06/2019] [Indexed: 01/23/2023]
Abstract
Acute and persistent pain are recognized consequences of TBI that can enhance suffering and significantly impair rehabilitative efforts. Both experimental models and clinical studies suggest that TBI may result in an imbalance between descending pain facilitatory and inhibitory pathways. The aim of this study was to assess the role of enhanced descending serotonin-mediated pain facilitation in a rat TBI model using selective spinal serotonergic fiber depletion with 5, 7-dihydroxytryptamine (DHT). We observed significant hindpaw allodynia in TBI rats that was reduced after DHT but not vehicle treatment. Immunohistochemical studies demonstrated profound spinal serotonin depletion in DHT-treated rats. Furthermore, lumbar intrathecal administration of the 5-HT3 receptor antagonist ondansetron at 7 days post-injury (DPI), when hindpaw allodynia was maximal, also attenuated nociceptive sensitization. Additional immunohistochemical analyses of the lumbar spinal cord at 7 DPI revealed a robust bilateral microglial response in the superficial dorsal horns that was significantly reduced with DHT treatment. Furthermore, serotonin depletion also prevented the TBI-induced bilateral increase in c-Fos positive cells within the Rexed laminae I and II of the dorsal horns. These results indicate that in the weeks following TBI, pain may be responsive to 5-HT3 receptor antagonists or other measures which rebalance descending pain modulation.
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25
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Martín M, Béjar J, Chávez D, Ramírez-Morales A, Hernández E, Moreno L, Contreras-Hernández E, Glusman S, Cortés U, Rudomin P. Supraspinal Shaping of Adaptive Transitions in the State of Functional Connectivity Between Segmentally Distributed Dorsal Horn Neuronal Populations in Response to Nociception and Antinociception. Front Syst Neurosci 2019; 13:47. [PMID: 31616259 PMCID: PMC6775247 DOI: 10.3389/fnsys.2019.00047] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 08/26/2019] [Indexed: 11/13/2022] Open
Abstract
In the anesthetized cat the correlation between the ongoing cord dorsum potentials (CDPs) recorded from different lumbar spinal segments has a non-random structure, suggesting relatively stable patterns of functional connectivity between the dorsal horn neuronal ensembles involved in the generation of these potentials. During the nociception induced by the intradermic injection of capsaicin, the patterns of segmental correlation between the spontaneous CDPs acquire other non-random configurations that are temporarily reversed to their pre-capsaicin state by the systemic injection of lidocaine, a procedure known to decrease the manifestation of neuropathic pain in both animals and humans. We have now extended these studies and utilized machine learning for the automatic extraction and selection of particular classes of CDPs according to their shapes and amplitudes. By using a Markovian analysis, we disclosed the transitions between the different kinds of CDPs induced by capsaicin and lidocaine and constructed a global model based on the changes in the behavior of the CDPs generated along the whole set of lumbar segments. This allowed the identification of the different states of functional connectivity within the whole ensemble of dorsal horn neurones attained during nociception and their transitory reversal by systemic administration of lidocaine in preparations with the intact neuroaxis and after spinalization. The present observations provide additional information on the state of self-organized criticality that leads to the adaptive behavior of the dorsal horn neuronal networks during nociception and antinociception both shaped by supraspinal descending influences.
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Affiliation(s)
- Mario Martín
- BarcelonaTech, Universitat Politècnica de Catalunya, Catalonia, Spain.,Barcelona Supercomputing Center, Catalonia, Spain
| | - Javier Béjar
- BarcelonaTech, Universitat Politècnica de Catalunya, Catalonia, Spain.,Barcelona Supercomputing Center, Catalonia, Spain
| | - Diógenes Chávez
- Department of Physiology, Biophysics and Neurosciences, Center for Research and Advanced Studies, National Polytechnic Institute, Mexico City, Mexico
| | - Adrian Ramírez-Morales
- Department of Physiology, Biophysics and Neurosciences, Center for Research and Advanced Studies, National Polytechnic Institute, Mexico City, Mexico
| | - Edson Hernández
- Department of Physiology, Biophysics and Neurosciences, Center for Research and Advanced Studies, National Polytechnic Institute, Mexico City, Mexico
| | - Leonardo Moreno
- Department of Physiology, Biophysics and Neurosciences, Center for Research and Advanced Studies, National Polytechnic Institute, Mexico City, Mexico
| | - Enrique Contreras-Hernández
- Department of Physiology, Biophysics and Neurosciences, Center for Research and Advanced Studies, National Polytechnic Institute, Mexico City, Mexico
| | - Silvio Glusman
- Department of Physiology, Biophysics and Neurosciences, Center for Research and Advanced Studies, National Polytechnic Institute, Mexico City, Mexico.,Stroger Cook County Hospital, Chicago, IL, United States
| | - Ulises Cortés
- BarcelonaTech, Universitat Politècnica de Catalunya, Catalonia, Spain.,Barcelona Supercomputing Center, Catalonia, Spain
| | - Pablo Rudomin
- Department of Physiology, Biophysics and Neurosciences, Center for Research and Advanced Studies, National Polytechnic Institute, Mexico City, Mexico.,El Colegio Nacional, Mexico City, Mexico
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26
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Nguyen HTT, Cho DH, Jang SH, Han SK, Park SJ. Potentiation of the glycine response by serotonin on the substantia gelatinosa neurons of the trigeminal subnucleus caudalis in mice. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2019; 23:271-279. [PMID: 31297011 PMCID: PMC6609265 DOI: 10.4196/kjpp.2019.23.4.271] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 06/05/2019] [Accepted: 06/07/2019] [Indexed: 01/06/2023]
Abstract
The lamina II, also called the substantia gelatinosa (SG), of the trigeminal subnucleus caudalis (Vc), is thought to play an essential role in the control of orofacial nociception. Glycine and serotonin (5-hydroxytryptamine, 5-HT) are the important neurotransmitters that have the individual parts on the modulation of nociceptive transmission. However, the electrophysiological effects of 5-HT on the glycine receptors on SG neurons of the Vc have not been well studied yet. For this reason, we applied the whole-cell patch clamp technique to explore the interaction of intracellular signal transduction between 5-HT and the glycine receptors on SG neurons of the Vc in mice. In nine of 13 neurons tested (69.2%), pretreatment with 5-HT potentiated glycine-induced current (IGly). Firstly, we examined with a 5-HT1 receptor agonist (8-OH-DPAT, 5-HT1/7 agonist, co-applied with SB-269970, 5-HT7 antagonist) and antagonist (WAY-100635), but 5-HT1 receptor agonist did not increase IGly and in the presence of 5-HT1 antagonist, the potentiation of 5-HT on IGly still happened. However, an agonist (α-methyl-5-HT) and antagonist (ketanserin) of the 5-HT2 receptor mimicked and inhibited the enhancing effect of 5-HT on IGly in the SG neurons, respectively. We also verified the role of the 5-HT7 receptor by using a 5-HT7 antagonist (SB-269970) but it also did not block the enhancement of 5-HT on IGly. Our study demonstrated that 5-HT facilitated IGly in the SG neurons of the Vc through the 5-HT2 receptor. The interaction between 5-HT and glycine appears to have a significant role in modulating the transmission of the nociceptive pathway.
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Affiliation(s)
- Hoang Thi Thanh Nguyen
- Department of Oral Physiology, School of Dentistry and Institute of Oral Bioscience, Chonbuk National University, Jeonju 54896, Korea
| | - Dong Hyu Cho
- Department of Obstetrics and Gynecology, Chonbuk National University Hospital and School of Medicine, Jeonju 54896, Korea
| | - Seon Hui Jang
- Department of Oral Physiology, School of Dentistry and Institute of Oral Bioscience, Chonbuk National University, Jeonju 54896, Korea
| | - Seong Kyu Han
- Department of Oral Physiology, School of Dentistry and Institute of Oral Bioscience, Chonbuk National University, Jeonju 54896, Korea
| | - Soo Joung Park
- Department of Oral Physiology, School of Dentistry and Institute of Oral Bioscience, Chonbuk National University, Jeonju 54896, Korea
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27
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Micheli L, Cialdai F, Pacini A, Branca JJV, Morbidelli L, Ciccone V, Lucarini E, Ghelardini C, Monici M, Di Cesare Mannelli L. Effect of NIR laser therapy by MLS-MiS source against neuropathic pain in rats: in vivo and ex vivo analysis. Sci Rep 2019; 9:9297. [PMID: 31243320 PMCID: PMC6594937 DOI: 10.1038/s41598-019-45469-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 06/03/2019] [Indexed: 12/26/2022] Open
Abstract
Neuropathic pain is characterized by an uncertain etiology and by a poor response to common therapies. The ineffectiveness and the frequent side effects of the drugs used to counteract neuropathic pain call for the discovery of new therapeutic strategies. Laser therapy proved to be effective for reducing pain sensitivity thus improving the quality of life. However, its application parameters and efficacy in chronic pain must be further analyzed. We investigated the pain relieving and protective effect of Photobiomodulation Therapy in a rat model of compressive mononeuropathy induced by Chronic Constriction Injury of the sciatic nerve (CCI). Laser (MLS-MiS) applications started 7 days after surgery and were performed ten times over a three week period showing a reduction in mechanical hypersensitivity and spontaneous pain that started from the first laser treatment until the end of the experiment. The ex vivo analysis highlighted the protective role of laser through the myelin sheath recovery in the sciatic nerve, inhibition of iNOS expression and enhancement of EAAT-2 levels in the spinal cord. In conclusion, this study supports laser treatment as a future therapeutic strategy in patients suffering from neuropathic pain induced by trauma.
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Affiliation(s)
- Laura Micheli
- Department of Neuroscience, Psychology, Drug Research and Child Health - NEUROFARBA - Pharmacology and Toxicology Section, University of Florence, Florence, Italy
| | - Francesca Cialdai
- ASAcampus Joint Laboratory, ASA Res. Div. - Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Alessandra Pacini
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | | | | | - Valerio Ciccone
- Department of Life Sciences, University of Siena, Siena, Italy
| | - Elena Lucarini
- Department of Neuroscience, Psychology, Drug Research and Child Health - NEUROFARBA - Pharmacology and Toxicology Section, University of Florence, Florence, Italy
| | - Carla Ghelardini
- Department of Neuroscience, Psychology, Drug Research and Child Health - NEUROFARBA - Pharmacology and Toxicology Section, University of Florence, Florence, Italy
| | - Monica Monici
- ASAcampus Joint Laboratory, ASA Res. Div. - Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Lorenzo Di Cesare Mannelli
- Department of Neuroscience, Psychology, Drug Research and Child Health - NEUROFARBA - Pharmacology and Toxicology Section, University of Florence, Florence, Italy.
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28
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Ni HD, Xu LS, Wang Y, Li H, An K, Liu M, Liu Q, Deng H, He Q, Huang B, Fang J, Yao M. Astrocyte activation in the periaqueductal gray promotes descending facilitation to cancer-induced bone pain through the JNK MAPK signaling pathway. Mol Pain 2019; 15:1744806919831909. [PMID: 30700204 PMCID: PMC6388461 DOI: 10.1177/1744806919831909] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Descending nociceptive modulation from the supraspinal structures has an important role in cancer-induced bone pain (CIBP). Midbrain ventrolateral periaqueductal gray (vlPAG) is a critical component of descending nociceptive circuits; nevertheless, its precise cellular and molecular mechanisms involved in descending facilitation remain elusive. Our previous study has shown that the activation of p38 MAPK in vlPAG microglia is essential for the neuropathic pain sensitization. However, the existence of potential connection between astrocytes and c-Jun N-terminal kinase (JNK) pathway in CIBP has not yet been elucidated. The following study examines the involvement of astrocyte activation and upregulation of p-JNK in vlPAG, using a CIBP rat model. Briefly, CIBP was mimicked by an intramedullary injection of Walker 256 mammary gland carcinoma cells into the animal tibia. A significant increase in expression levels of astrocytes in the vlPAG of CIBP rats was observed. Furthermore, stereotaxic microinjection of the astrocytic cytotoxin L-α-aminoadipic acid decreased the mechanical allodynia as well as established and reversed the astrocyte activation in CIBP rats. A significant increase in expression levels of p-JNK in astrocytes in vlPAG of CIBP rats was also observed. Moreover, the intrathecal administration of JNK inhibitors SP600125 reduced the expression of glial fibrillary acidic protein, while microinjection of the SP600125 decreased the mechanical allodynia of CIBP rats. These results suggested that CIBP is associated with astrocyte activation in the vlPAG that probably participates in driving descending pain facilitation through the JNK MAPK signaling pathway. To sum up, these findings reveal a novel site of astrocytes modulation of CIBP.
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Affiliation(s)
- Hua-Dong Ni
- 1 The Second Clinical Medical College, Zhejiang Chinese Medicine University, Hangzhou, China.,2 Department of Anesthesiology and Pain Research Center, The First Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Long Sheng Xu
- 2 Department of Anesthesiology and Pain Research Center, The First Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Yungong Wang
- 2 Department of Anesthesiology and Pain Research Center, The First Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Hongbo Li
- 2 Department of Anesthesiology and Pain Research Center, The First Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Kang An
- 3 Department of Anesthesiology, Bengbu Medical College, Bengbu, China
| | - Mingjuan Liu
- 2 Department of Anesthesiology and Pain Research Center, The First Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Qianying Liu
- 3 Department of Anesthesiology, Bengbu Medical College, Bengbu, China
| | - Houshen Deng
- 2 Department of Anesthesiology and Pain Research Center, The First Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Qiuli He
- 2 Department of Anesthesiology and Pain Research Center, The First Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Bing Huang
- 2 Department of Anesthesiology and Pain Research Center, The First Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Jianqiao Fang
- 1 The Second Clinical Medical College, Zhejiang Chinese Medicine University, Hangzhou, China
| | - Ming Yao
- 2 Department of Anesthesiology and Pain Research Center, The First Affiliated Hospital of Jiaxing University, Jiaxing, China
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Yao PW, Wang SK, Chen SX, Xin WJ, Liu XG, Zang Y. Upregulation of tumor necrosis factor-alpha in the anterior cingulate cortex contributes to neuropathic pain and pain-associated aversion. Neurobiol Dis 2019; 130:104456. [PMID: 31028871 DOI: 10.1016/j.nbd.2019.04.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 04/10/2019] [Accepted: 04/23/2019] [Indexed: 10/26/2022] Open
Abstract
Injury associated pain involves subjective perception and emotional experience. The anterior cingulate cortex (ACC) is a key area involved in the affective component of pain processing. However, the neuroimmune mechanisms underlying enhanced ACC excitability following peripheral nerve injury are still not fully understood. Our previous work has shown that tumor necrosis factor-alpha (TNF-α) overexpression leads to peripheral afferent hyperexcitability and synaptic transmission potentiation in spinal cord. Here, we aimed to reveal the potential role of ACC TNF-α in ACC hyperexcitability and neuropathic pain. c-Fos, a widely used neuronal activity marker, was induced especially in contralateral ACC early [postoperative (PO) 1 h] and later (PO day 7 and 10) during the development of neuropathic pain. Spared nerve injury (SNI) elevated TNF-α level in contralateral ACC from PO day 5 to 14, delayed relative to decreased ipsilateral paw withdrawal threshold apparent from PO day 1 to 14. Microinjection of anti-TNF-α antibody into the ACC completely eliminated c-Fos overexpression and greatly attenuated pain aversion and mechanical allodynia induced by SNI, suggesting an important role of ACC TNF-α in the pain aversiveness and pain maintenance. Furthermore, modulating ACC pyramidal neurons via a Gi-coupled human M4 muscarinic receptor (hM4Di) or a Gq-coupled human M3 muscarinic receptor (hM3Dq), a type of designer receptors exclusively activated by designer drugs (DREADD), greatly changed the ACC TNF-α level and the mechanical paw withdrawal threshold. The positive interactions between TNF-α and ACC neurons might modulate the cytokine microenvironment thus contribute to the neuropathic pain.
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Affiliation(s)
- Pei-Wen Yao
- Pain Research Center and Department of Physiology, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, PR China
| | - Shao-Kun Wang
- Pain Research Center and Department of Physiology, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, PR China
| | - Shao-Xia Chen
- Pain Research Center and Department of Physiology, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, PR China; Department of Anesthesiology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, PR China
| | - Wen-Jun Xin
- Pain Research Center and Department of Physiology, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, PR China
| | - Xian-Guo Liu
- Pain Research Center and Department of Physiology, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, PR China
| | - Ying Zang
- Pain Research Center and Department of Physiology, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, PR China.
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30
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Src activation in the hypothalamic arcuate nucleus may play an important role in pain hypersensitivity. Sci Rep 2019; 9:3827. [PMID: 30846840 PMCID: PMC6405746 DOI: 10.1038/s41598-019-40572-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 02/15/2019] [Indexed: 12/30/2022] Open
Abstract
Src family of kinases (SFKs) has been found to play an important role in the regulation of nociception. However, how each member of this family acts in the central nervous system (CNS) structures involved in the relay and/or modulation of nociceptive signals, and thereby contributes to the formation and maintenance of pain hypersensitivity, is still a challenge. In this work, a combined study using biochemical, genetic and behavioral approaches was conducted. We found that the expression of activated SFKs in the hypothalamic arcuate nucleus (ARC) area was significantly increased following the development of inflammation induced by injection of complete freund's adjuvant (CFA) into the hind paw of rats. Furthermore, we identified that Src, but not Fyn or Lyn in the Src family, was activated, and that Src knockdown in the ARC area blocked the inflammation-induced increases in the expression of activated SFKs, the N-Methyl-D-aspartate receptor (NMDAR) GluN2B subunit and phosphorylated GluN2B at Y1472 in this region. Moreover, the CFA injection-induced allodynia and hyperalgesia, and the analgesic effect produced by systemic application of the SFK inhibitor, SU6656, were significantly diminished. However, the Src knockdown did not induce any change in the expression of activated SFKs and the NMDAR GluN2B subunit in normal rats which were not injected with CFA. Neither the Src knockdown nor the systemic application of SU6656 affected the mechanical and thermal sensitivity of the normal rats. Thus, Src activation in the ARC may be a key event for formation and maintenance of pain hypersensitivity associated with peripheral inflammation.
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31
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Wang W, Zhong X, Li Y, Guo R, Du S, Wen L, Ying Y, Yang T, Wei X. Rostral ventromedial medulla‐mediated descending facilitation following P2X7 receptor activation is involved in the development of chronic post‐operative pain. J Neurochem 2019; 149:760-780. [DOI: 10.1111/jnc.14650] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 10/14/2018] [Accepted: 12/12/2018] [Indexed: 12/30/2022]
Affiliation(s)
- Wei Wang
- Department of Physiology and Pain Research Center Zhongshan School of Medicine Sun Yat‐sen University Guangzhou Guangdong People's Republic of China
| | - Xiongxiong Zhong
- Department of Physiology and Pain Research Center Zhongshan School of Medicine Sun Yat‐sen University Guangzhou Guangdong People's Republic of China
| | - Yongyong Li
- Department of Physiology and Pain Research Center Zhongshan School of Medicine Sun Yat‐sen University Guangzhou Guangdong People's Republic of China
| | - Ruixian Guo
- Department of Physiology and Pain Research Center Zhongshan School of Medicine Sun Yat‐sen University Guangzhou Guangdong People's Republic of China
- Guangdong Provincial Key Laboratory of Brain Function and Disease Guangzhou Guangdong People's Republic of China
| | - Sujuan Du
- Department of Anesthesiology Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou China
| | - Lili Wen
- Department of Anesthesiology Cancer Center State Key Laboratory of Oncology in South China Collaborative, Innovation Center for Cancer Medicine Sun Yat‐sen University Guangzhou P. R. China
| | - Yanlu Ying
- Department of Anesthesiology Guangzhou First People's Hospital Guangzhou Medical University Guangzhou China
| | - Tao Yang
- Department of Anesthesiology Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou China
| | - Xu‐Hong Wei
- Department of Physiology and Pain Research Center Zhongshan School of Medicine Sun Yat‐sen University Guangzhou Guangdong People's Republic of China
- Guangdong Provincial Key Laboratory of Brain Function and Disease Guangzhou Guangdong People's Republic of China
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32
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Ni H, Wang Y, An K, Liu Q, Xu L, Zhu C, Deng H, He Q, Wang T, Xu M, Zheng Y, Huang B, Fang J, Yao M. Crosstalk between NFκB-dependent astrocytic CXCL1 and neuron CXCR2 plays a role in descending pain facilitation. J Neuroinflammation 2019; 16:1. [PMID: 30606213 PMCID: PMC6317220 DOI: 10.1186/s12974-018-1391-2] [Citation(s) in RCA: 109] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Accepted: 12/17/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Despite accumulating evidence on the role of glial cells and their associated chemicals in mechanisms of pain, few studies have addressed the potential role of chemokines in the descending facilitation of chronic pain. We aimed to study the hypothesis that CXCL1/CXCR2 axis in the periaqueductal gray (PAG), a co-restructure of the descending nociceptive system, is involved in descending pain facilitation. METHODS Intramedullary injection of Walker 256 mammary gland carcinoma cells of adult female Sprague Dawley rats was used to establish a bone cancer pain (BCP) model. RT-PCR, Western blot, and immunohistochemistry were performed to detect pNfkb, Cxcl1, and Cxcr2 and their protein expression in the ventrolateral PAG (vlPAG). Immunohistochemical co-staining with NeuN, GFAP, and CD11 were used to examine the cellular location of pNFκB, CXCL1, and CXCR2. The effects of NFκB and CXCR2 antagonists and CXCL1 neutralizing antibody on pain hypersensitivity were evaluated by behavioral testing. RESULTS BCP induced cortical bone damage and persistent mechanical allodynia and increased the expression of pNFκB, CXCL1, and CXCR2 in vlPAG. The induced phosphorylation of NFκB was co-localized with GFAP and NeuN, but not with CD11. Micro-injection of BAY11-7082 attenuated BCP and reduced CXCL1 increase in the spinal cord. The expression level of CXCL1 in vlPAG showed co-localization with GFAP, but not with CD11 and NeuN. Micro-administration of CXCL1 neutralizing antibody from 6 to 9 days after inoculation attenuated mechanical allodynia. Furthermore, vlPAG application of CXCL1 elicited pain hypersensitivity in normal rats. Interestingly, CXCR2 was upregulated in vlPAG neurons (not with CD11 and GFAP) after BCP. CXCR2 antagonist SB225002 completely blocked the CXCL1-induced mechanical allodynia and attenuated BCP-induced pain hypersensitivity. CONCLUSION The NFκB-dependent CXCL1-CXCR2 signaling cascade played a role in glial-neuron interactions and in descending facilitation of BCP.
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Affiliation(s)
- Huadong Ni
- Department of Anesthesiology and Pain Research center, The First Affiliated Hospital of Jiaxing University, Jiaxing, 314001 China
| | - Yungong Wang
- Department of Anesthesiology, Zhuzhou Central Hospital, Zhuzhou, 412000 China
| | - Kang An
- Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, 210004 China
| | - Qianying Liu
- Department of Anesthesiology and Pain Research center, The First Affiliated Hospital of Jiaxing University, Jiaxing, 314001 China
| | - Longsheng Xu
- Department of Anesthesiology and Pain Research center, The First Affiliated Hospital of Jiaxing University, Jiaxing, 314001 China
| | - Chunyan Zhu
- Department of Anesthesiology and Pain Research center, The First Affiliated Hospital of Jiaxing University, Jiaxing, 314001 China
| | - Housheng Deng
- Department of Anesthesiology and Pain Research center, The First Affiliated Hospital of Jiaxing University, Jiaxing, 314001 China
| | - Qiuli He
- Department of Anesthesiology and Pain Research center, The First Affiliated Hospital of Jiaxing University, Jiaxing, 314001 China
| | - Tingting Wang
- Department of Anesthesiology and Pain Research center, The First Affiliated Hospital of Jiaxing University, Jiaxing, 314001 China
| | - Miao Xu
- Department of Anesthesiology and Pain Research center, The First Affiliated Hospital of Jiaxing University, Jiaxing, 314001 China
| | - Ying Zheng
- Department of Anesthesiology and Pain Research center, The First Affiliated Hospital of Jiaxing University, Jiaxing, 314001 China
| | - Bing Huang
- Department of Anesthesiology and Pain Research center, The First Affiliated Hospital of Jiaxing University, Jiaxing, 314001 China
| | - Jianqiao Fang
- Zhejiang Chinese Medicine University, Hangzhou, 310053 China
| | - Ming Yao
- Department of Anesthesiology and Pain Research center, The First Affiliated Hospital of Jiaxing University, Jiaxing, 314001 China
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Bravo L, Llorca-Torralba M, Berrocoso E, Micó JA. Monoamines as Drug Targets in Chronic Pain: Focusing on Neuropathic Pain. Front Neurosci 2019; 13:1268. [PMID: 31942167 PMCID: PMC6951279 DOI: 10.3389/fnins.2019.01268] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 11/08/2019] [Indexed: 12/11/2022] Open
Abstract
Monoamines are involved in regulating the endogenous pain system and indeed, peripheral and central monoaminergic dysfunction has been demonstrated in certain types of pain, particularly in neuropathic pain. Accordingly, drugs that modulate the monaminergic system and that were originally designed to treat depression are now considered to be first line treatments for certain types of neuropathic pain (e.g., serotonin and noradrenaline (and also dopamine) reuptake inhibitors). The analgesia induced by these drugs seems to be mediated by inhibiting the reuptake of these monoamines, thereby reinforcing the descending inhibitory pain pathways. Hence, it is of particular interest to study the monoaminergic mechanisms involved in the development and maintenance of chronic pain. Other analgesic drugs may also be used in combination with monoamines to facilitate descending pain inhibition (e.g., gabapentinoids and opioids) and such combinations are often also used to alleviate certain types of chronic pain. By contrast, while NSAIDs are thought to influence the monoaminergic system, they just produce consistent analgesia in inflammatory pain. Thus, in this review we will provide preclinical and clinical evidence of the role of monoamines in the modulation of chronic pain, reviewing how this system is implicated in the analgesic mechanism of action of antidepressants, gabapentinoids, atypical opioids, NSAIDs and histaminergic drugs.
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Affiliation(s)
- Lidia Bravo
- Neuropsychopharmacology and Psychobiology Research Group, Department of Neuroscience, University of Cádiz, Cádiz, Spain
- Instituto de Investigación e Innovación Biomédica de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Cádiz, Spain
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
| | - Meritxell Llorca-Torralba
- Neuropsychopharmacology and Psychobiology Research Group, Department of Neuroscience, University of Cádiz, Cádiz, Spain
- Instituto de Investigación e Innovación Biomédica de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Cádiz, Spain
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
| | - Esther Berrocoso
- Instituto de Investigación e Innovación Biomédica de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Cádiz, Spain
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
- Neuropsychopharmacology and Psychobiology Research Group, Department of Psychology, University of Cádiz, Cádiz, Spain
| | - Juan Antonio Micó
- Neuropsychopharmacology and Psychobiology Research Group, Department of Neuroscience, University of Cádiz, Cádiz, Spain
- Instituto de Investigación e Innovación Biomédica de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Cádiz, Spain
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
- *Correspondence: Juan Antonio Micó,
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Predictive Factors for Developing Chronic Pain After Total Knee Arthroplasty. J Arthroplasty 2018; 33:3372-3378. [PMID: 30143334 DOI: 10.1016/j.arth.2018.07.028] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 07/28/2018] [Indexed: 02/01/2023] Open
Abstract
Total knee arthroplasty offers substantial improvements for patients as measured by functional status and quality of life; however, 8% to 34% of patients experience chronic postsurgical pain following surgery (CPSP). In addition to disruption in daily activities of life caused by the pain itself, CPSP has been associated with an overall reduction in quality of life following surgery. Risk factors for CPSP can be broadly defined as potentially modifiable or unlikely modifiable. Unlikely modifiable risks include gender, age, medical comorbidities, and socioeconomic status. Potentially modifiable risks include perioperative pain, physical function, psychological state, surgical factors, and possibly genomics. Understanding risks and the magnitude of their effect on outcomes such as CPSP is desirable because interventions designed to affect these factors may be able to dramatically improve outcomes.
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Merighi A. The histology, physiology, neurochemistry and circuitry of the substantia gelatinosa Rolandi (lamina II) in mammalian spinal cord. Prog Neurobiol 2018; 169:91-134. [PMID: 29981393 DOI: 10.1016/j.pneurobio.2018.06.012] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Revised: 06/07/2018] [Accepted: 06/30/2018] [Indexed: 02/06/2023]
Abstract
The substantia gelatinosa Rolandi (SGR) was first described about two centuries ago. In the following decades an enormous amount of information has permitted us to understand - at least in part - its role in the initial processing of pain and itch. Here, I will first provide a comprehensive picture of the histology, physiology, and neurochemistry of the normal SGR. Then, I will analytically discuss the SGR circuits that have been directly demonstrated or deductively envisaged in the course of the intensive research on this area of the spinal cord, with particular emphasis on the pathways connecting the primary afferent fibers and the intrinsic neurons. The perspective existence of neurochemically-defined sets of primary afferent neurons giving rise to these circuits will be also discussed, with the proposition that a cross-talk between different subsets of peptidergic fibers may be the structural and functional substrate of additional gating mechanisms in SGR. Finally, I highlight the role played by slow acting high molecular weight modulators in these gating mechanisms.
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Affiliation(s)
- Adalberto Merighi
- Department of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2, I-10095 Grugliasco (TO), Italy.
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Gainfully employing descending controls in acute and chronic pain management. Vet J 2018; 237:16-25. [DOI: 10.1016/j.tvjl.2018.05.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 05/15/2018] [Accepted: 05/16/2018] [Indexed: 12/30/2022]
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Contreras‐Hernández E, Chávez D, Hernández E, Velázquez E, Reyes P, Béjar J, Martín M, Cortés U, Glusman S, Rudomin P. Supraspinal modulation of neuronal synchronization by nociceptive stimulation induces an enduring reorganization of dorsal horn neuronal connectivity. J Physiol 2018; 596:1747-1776. [PMID: 29451306 PMCID: PMC5924834 DOI: 10.1113/jp275228] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Accepted: 02/12/2018] [Indexed: 12/21/2022] Open
Abstract
KEY POINTS The state of central sensitization induced by the intradermic injection of capsaicin leads to structured (non-random) changes in functional connectivity between dorsal horn neuronal populations distributed along the spinal lumbar segments in anaesthetized cats. The capsaicin-induced changes in neuronal connectivity and the concurrent increase in secondary hyperalgesia are transiently reversed by the systemic administration of small doses of lidocaine, a clinically effective procedure to treat neuropathic pain. The effects of both capsaicin and lidocaine are greatly attenuated in spinalized preparations, showing that supraspinal influences play a significant role in the shaping of nociceptive-induced changes in dorsal horn functional neuronal connectivity. We conclude that changes in functional connectivity between segmental populations of dorsal horn neurones induced by capsaicin and lidocaine result from a cooperative adaptive interaction between supraspinal and spinal neuronal networks, a process that may have a relevant role in the pathogenesis of chronic pain and analgesia. ABSTRACT Despite a profusion of information on the molecular and cellular mechanisms involved in the central sensitization produced by intense nociceptive stimulation, the changes in the patterns of functional connectivity between spinal neurones associated with the development of secondary hyperalgesia and allodynia remain largely unknown. Here we show that the state of central sensitization produced by the intradermal injection of capsaicin is associated with structured transformations in neuronal synchronization that lead to an enduring reorganization of the functional connectivity within a segmentally distributed ensemble of dorsal horn neurones. These changes are transiently reversed by the systemic administration of small doses of lidocaine, a clinically effective procedure to treat neuropathic pain. Lidocaine also reduces the capsaicin-induced facilitation of the spinal responses evoked by weak mechanical stimulation of the skin in the region of secondary but not primary hyperalgesia. The effects of both intradermic capsaicin and systemic lidocaine on the segmental correlation and coherence between ongoing cord dorsum potentials and on the responses evoked by tactile stimulation in the region of secondary hyperalgesia are greatly attenuated in spinalized preparations, showing that supraspinal influences are involved in the reorganization of the nociceptive-induced structured patterns of dorsal horn neuronal connectivity. We conclude that the structured reorganization of the functional connectivity between the dorsal horn neurones induced by capsaicin nociceptive stimulation results from cooperative interactions between supraspinal and spinal networks, a process that may have a relevant role in the shaping of the spinal state in the pathogenesis of chronic pain and analgesia.
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Affiliation(s)
- E. Contreras‐Hernández
- Department of PhysiologyCentro de Investigación y de Estudios Avanzados del Instituto Politécnico NacionalMéxico
| | - D. Chávez
- Department of PhysiologyCentro de Investigación y de Estudios Avanzados del Instituto Politécnico NacionalMéxico
| | - E. Hernández
- Department of PhysiologyCentro de Investigación y de Estudios Avanzados del Instituto Politécnico NacionalMéxico
| | - E. Velázquez
- Department of PhysiologyCentro de Investigación y de Estudios Avanzados del Instituto Politécnico NacionalMéxico
| | - P. Reyes
- Department of PhysiologyCentro de Investigación y de Estudios Avanzados del Instituto Politécnico NacionalMéxico
| | - J. Béjar
- Universidad Politécnica de CatalunyaBarcelonaTechCataloniaSpain
| | - M. Martín
- Universidad Politécnica de CatalunyaBarcelonaTechCataloniaSpain
| | - U. Cortés
- Universidad Politécnica de CatalunyaBarcelonaTechCataloniaSpain
- Barcelona Supercomputing CenterCataloniaSpain
| | - S. Glusman
- Department of PhysiologyCentro de Investigación y de Estudios Avanzados del Instituto Politécnico NacionalMéxico
- Stroger Cook County HospitalChicagoIllinoisUSA
| | - P. Rudomin
- Department of PhysiologyCentro de Investigación y de Estudios Avanzados del Instituto Politécnico NacionalMéxico
- El Colegio NacionalMéxico
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Altered Excitability and Local Connectivity of mPFC-PAG Neurons in a Mouse Model of Neuropathic Pain. J Neurosci 2018; 38:4829-4839. [PMID: 29695413 DOI: 10.1523/jneurosci.2731-17.2018] [Citation(s) in RCA: 102] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Revised: 03/09/2018] [Accepted: 03/20/2018] [Indexed: 12/29/2022] Open
Abstract
The medial prefrontal cortex (mPFC) plays a major role in both sensory and affective aspects of pain. There is extensive evidence that chronic pain produces functional changes within the mPFC. However, our understanding of local circuit changes to defined subpopulations of mPFC neurons in chronic pain models remains unclear. A major subpopulation of mPFC neurons project to the periaqueductal gray (PAG), which is a key midbrain structure involved in endogenous pain suppression and facilitation. Here, we used laser scanning photostimulation of caged glutamate to map cortical circuits of retrogradely labeled cortico-PAG (CP) neurons in layer 5 (L5) of mPFC in brain slices prepared from male mice having undergone chronic constriction injury (CCI) of the sciatic nerve. Whole-cell recordings revealed a significant reduction in excitability for L5 CP neurons contralateral to CCI in the prelimbic (PL), but not infralimbic (IL), region of mPFC. Circuit mapping showed that excitatory inputs to L5 CP neurons in both PL and IL arose primarily from layer 2/3 (L2/3) and were significantly reduced in CCI mice. Glutamate stimulation of L2/3 and L5 elicited inhibitory inputs to CP neurons in both PL and IL, but only L2/3 input was significantly reduced in CP neurons of CCI mice. We also observed significant reduction in excitability and L2/3 inhibitory input to CP neurons ipsilateral to CCI. These results demonstrating region and laminar specific changes to mPFC-PAG neurons suggest that a unilateral CCI bilaterally alters cortical circuits upstream of the endogenous analgesic network, which may contribute to persistence of chronic pain.SIGNIFICANCE STATEMENT Chronic pain is a significant unresolved medical problem that is refractory to traditional analgesics and can negatively affect emotional health. The role of central circuits in mediating the persistent nature of chronic pain remains unclear. Local circuits within the medial prefrontal cortex (mPFC) process ascending pain inputs and can modulate endogenous analgesia via direct projections to the periaqueductal gray (PAG). However, the mechanisms by which chronic pain alters intracortical circuitry of mPFC-PAG neurons are unknown. Here, we report specific changes to local circuits of mPFC-PAG neurons in mice displaying chronic pain behavior after nerve injury. These findings provide evidence for a neural mechanism by which chronic pain disrupts the descending analgesic system via functional changes to cortical circuits.
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Wallden M, Chek P. The ghost in the machine – Is musculoskeletal medicine lacking soul? J Bodyw Mov Ther 2018; 22:438-448. [DOI: 10.1016/j.jbmt.2018.02.019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Affiliation(s)
- K. Hopster
- Department of Clinical Studies New Bolton Center School of Veterinary Medicine University of Pennsylvania Kennett Square Pennsylvania USA
| | - A. W. Eps
- Department of Clinical Studies New Bolton Center School of Veterinary Medicine University of Pennsylvania Kennett Square Pennsylvania USA
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Petrosino S, Cordaro M, Verde R, Schiano Moriello A, Marcolongo G, Schievano C, Siracusa R, Piscitelli F, Peritore AF, Crupi R, Impellizzeri D, Esposito E, Cuzzocrea S, Di Marzo V. Oral Ultramicronized Palmitoylethanolamide: Plasma and Tissue Levels and Spinal Anti-hyperalgesic Effect. Front Pharmacol 2018; 9:249. [PMID: 29615912 PMCID: PMC5870042 DOI: 10.3389/fphar.2018.00249] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 03/06/2018] [Indexed: 12/22/2022] Open
Abstract
Palmitoylethanolamide (PEA) is a pleiotropic lipid mediator with established anti-inflammatory and anti-hyperalgesic activity. Ultramicronized PEA (PEA-um) has superior oral efficacy compared to naïve (non-micronized) PEA. The aim of the present study was two-fold: (1) to evaluate whether oral PEA-um has greater absorbability compared to naïve PEA, and its ability to reach peripheral and central tissues under healthy and local inflammatory conditions (carrageenan paw edema); (2) to better characterize the molecular pathways involved in PEA-um action, particularly at the spinal level. Rats were dosed with 30 mg/kg of [13C]4-PEA-um or naïve [13C]4-PEA by oral gavage, and [13C]4-PEA levels quantified, as a function of time, by liquid chromatography/atmospheric pressure chemical ionization/mass spectrometry. Overall plasma levels were higher in both healthy and carrageenan-injected rats administered [13C]4-PEA-um as compared to those receiving naïve [13C]4-PEA, indicating the greater absorbability of PEA-um. Furthermore, carrageenan injection markedly favored an increase in levels of [13C]4-PEA in plasma, paw and spinal cord. Oral treatment of carrageenan-injected rats with PEA-um (10 mg/kg) confirmed beneficial peripheral effects on paw inflammation, thermal hyperalgesia and tissue damage. Notably, PEA-um down-regulated distinct spinal inflammatory and oxidative pathways. These last findings instruct on spinal mechanisms involved in the anti-hyperalgesic effect of PEA-um in inflammatory pain.
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Affiliation(s)
- Stefania Petrosino
- Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, Napoli, Italy
- Epitech Group SpA, Padova, Italy
| | - Marika Cordaro
- Department of Chemical, Biological, Pharmaceutical and Environmental Science University of Messina, Messina, Italy
| | - Roberta Verde
- Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, Napoli, Italy
| | - Aniello Schiano Moriello
- Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, Napoli, Italy
- Epitech Group SpA, Padova, Italy
| | | | | | - Rosalba Siracusa
- Department of Chemical, Biological, Pharmaceutical and Environmental Science University of Messina, Messina, Italy
| | - Fabiana Piscitelli
- Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, Napoli, Italy
| | - Alessio F. Peritore
- Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, Napoli, Italy
| | - Rosalia Crupi
- Department of Chemical, Biological, Pharmaceutical and Environmental Science University of Messina, Messina, Italy
| | - Daniela Impellizzeri
- Department of Chemical, Biological, Pharmaceutical and Environmental Science University of Messina, Messina, Italy
| | - Emanuela Esposito
- Department of Chemical, Biological, Pharmaceutical and Environmental Science University of Messina, Messina, Italy
| | - Salvatore Cuzzocrea
- Department of Chemical, Biological, Pharmaceutical and Environmental Science University of Messina, Messina, Italy
| | - Vincenzo Di Marzo
- Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, Napoli, Italy
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Harper DE, Ichesco E, Schrepf A, Hampson JP, Clauw DJ, Schmidt-Wilcke T, Harris RE, Harte SE. Resting Functional Connectivity of the Periaqueductal Gray Is Associated With Normal Inhibition and Pathological Facilitation in Conditioned Pain Modulation. THE JOURNAL OF PAIN 2018; 19:635.e1-635.e15. [PMID: 29360608 DOI: 10.1016/j.jpain.2018.01.001] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Revised: 12/18/2017] [Accepted: 01/03/2018] [Indexed: 12/14/2022]
Abstract
Conditioned pain modulation (CPM), a psychophysical paradigm that is commonly used to infer the integrity of endogenous pain-altering systems by observation of the effect of one noxious stimulus on another, has previously identified deficient endogenous analgesia in fibromyalgia (FM) and other chronic pain conditions. The mechanisms underlying this deficiency, be they insufficient inhibition and/or active facilitation, are largely unknown. The present cross-sectional study used a combination of behavioral CPM testing, voxel-based morphometry, and resting state functional connectivity to identify neural correlates of CPM in healthy controls (HC; n = 14) and FM patients (n = 15), and to probe for differences that could explain the pain-facilitative CPM that was observed in our patient sample. Voxel-based morphometry identified a cluster encompassing the periaqueductal gray (PAG) that contained significantly less gray matter volume in FM patients. Higher resting connectivity between this cluster and cortical pain processing regions was associated with more efficient inhibitory CPM in both groups, whereas PAG connectivity with the dorsal pons was associated with greater CPM inhibition only in HC. Greater PAG connectivity to the caudal pons/rostral medulla, which was pain-inhibitory in HC, was associated with pain facilitation in FM patients. PERSPECTIVE These findings indicate that variation in the strength of the PAG resting functional connectivity can explain some of the normal variability in CPM. In addition, pain-facilitative CPM observed in FM patients likely involves attenuation of pain inhibitory as well as amplification of pain facilitative processes in the central nervous system.
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Affiliation(s)
- Daniel E Harper
- Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan.
| | - Eric Ichesco
- Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan
| | - Andrew Schrepf
- Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan
| | - Johnson P Hampson
- Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan
| | - Daniel J Clauw
- Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan
| | - Tobias Schmidt-Wilcke
- Department of Neurology, St. Mauritius Therapieklinik, Meerbusch, Germany; Department of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Richard E Harris
- Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan
| | - Steven E Harte
- Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan
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Electroacupuncture Inhibits the Activation of p38MAPK in the Central Descending Facilitatory Pathway in Rats with Inflammatory Pain. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 2017:7531060. [PMID: 29358970 PMCID: PMC5735650 DOI: 10.1155/2017/7531060] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 09/15/2017] [Accepted: 11/01/2017] [Indexed: 12/30/2022]
Abstract
The mitogen-activated protein kinases (MAPKs), especially p38MAPK, play a pivotal role in chronic pain. Electroacupuncture (EA) relieves inflammatory pain underlying the descending pathway, that is, the periaqueductal gray (PAG), the rostral ventromedial medulla (RVM), and the spinal cord dorsal horn (SCDH). However, whether EA antagonizes inflammatory pain through regulation of p38MAPK in this descending facilitatory pathway is unclear. Complete Freund's adjuvant (CFA) was injected into the hind paw of rats to establish inflammatory pain model. EA was administrated for 30 min at Zusanli and Kunlun acupoints at 0.5, 24.5, 48.5, and 72.5 h, respectively. The paw withdrawal threshold (PWT), paw edema, and Phosphor-p38MAPK-Immunoreactivity (p-p38MAPK-IR) cells were measured before (0 h) and at 1, 3, 5, 7, 25, and 73 h after CFA or saline injection. EA increased PWT at 1, 3, 25, and 73 h and inhibited paw edema at 25 and 73 h after CFA injection. Moreover, the increasing number of p-p38MAPK-IR cells which was induced by CFA was suppressed by EA stimulation in PAG and RVM at 3 and 5 h and in SCDH at 5, 7, 25, and 73 h. These results suggest that EA suppresses inflammation-induced hyperalgesia probably through inhibiting p38MAPK activation in the descending facilitatory pathway.
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Abstract
The rostral ventromedial medulla (RVM) has a well-documented role in pain modulation and exerts antinociceptive and pronociceptive influences mediated by 2 distinct classes of neurons, OFF-cells and ON-cells. OFF-cells are defined by a sudden pause in firing in response to nociceptive inputs, whereas ON-cells are characterized by a "burst" of activity. Although these reflex-related changes in ON- and OFF-cell firing are critical to their pain-modulating function, the pathways mediating these responses have not been identified. The present experiments were designed to test the hypothesis that nociceptive input to the RVM is relayed through the parabrachial complex (PB). In electrophysiological studies, ON- and OFF-cells were recorded in the RVM of lightly anesthetized male rats before and after an infusion of lidocaine or muscimol into PB. The ON-cell burst and OFF-cell pause evoked by noxious heat or mechanical probing were substantially attenuated by inactivation of the lateral, but not medial, parabrachial area. Retrograde tracing studies showed that neurons projecting to the RVM were scattered throughout PB. Few of these neurons expressed calcitonin gene-related peptide, suggesting that the RVM projection from PB is distinct from that to the amygdala. These data show that a substantial component of "bottom-up" nociceptive drive to RVM pain-modulating neurons is relayed through the PB. While the PB is well known as an important relay for ascending nociceptive information, its functional connection with the RVM allows the spinoparabrachial pathway to access descending control systems as part of a recurrent circuit.
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Wang CT, Mao CJ, Zhang XQ, Zhang CY, Lv DJ, Yang YP, Xia KL, Liu JY, Wang F, Hu LF, Xu GY, Liu CF. Attenuation of hyperalgesia responses via the modulation of 5-hydroxytryptamine signalings in the rostral ventromedial medulla and spinal cord in a 6-hydroxydopamine-induced rat model of Parkinson's disease. Mol Pain 2017; 13:1744806917691525. [PMID: 28326933 PMCID: PMC5302179 DOI: 10.1177/1744806917691525] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Background Although pain is one of the most distressing non-motor symptoms among patients with Parkinson's disease, the underlying mechanisms of pain in Parkinson's disease remain elusive. The aim of the present study was to investigate the role of serotonin (5-hydroxytryptamine) in the rostral ventromedial medulla (RVM) and spinal cord in pain sensory abnormalities in a 6-hydroxydopamine-treated rat model of Parkinson's disease. Methods The rotarod test was used to evaluate motor function. The radiant heat test and von Frey test were conducted to evaluate thermal and mechanical pain thresholds, respectively. Immunofluorescence was used to examine 5-hydroxytryptamine neurons and fibers in the rostral ventromedial medulla and spinal cord. High-performance liquid chromatography was used to determine 5-hydroxytryptamine and 5-hydroxyindoleacetic acid levels. Results The duration of running time on the rotarod test was significantly reduced in 6-hydroxydopamine-treated rats. Nociceptive thresholds of both mechanical and heat pain were reduced compared to sham-treated rats. In addition to the degeneration of cell bodies and fibers in the substantia nigra pars compacta, the number of rostral ventromedial medulla 5-hydroxytryptamine neurons and 5-hydroxytryptamine fibers in the spinal dorsal horn was dramatically decreased. 5-Hydroxytryptamine concentrations in both the rostral ventromedial medulla and spinal cord were reduced. Furthermore, the administration of citalopram significantly attenuated pain hypersensitivity. Interestingly, Intra-rostral ventromedial medulla (intra-RVM) microinjection of 5,7-dihydroxytryptamine partially reversed pain hypersensitivity of 6-hydroxydopamine-treated rats. Conclusions These results suggest that the decreased 5-hydroxytryptamine contents in the rostral ventromedial medulla and spinal dorsal horn may be involved in hyperalgesia in the 6-hydroxydopamine-induced rat model of Parkinson's disease.
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Affiliation(s)
- Chen-Tao Wang
- 1 Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China.,2 Institute of Neuroscience, Soochow University, Suzhou, China
| | - Cheng-Jie Mao
- 1 Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiao-Qi Zhang
- 2 Institute of Neuroscience, Soochow University, Suzhou, China
| | - Cai-Yi Zhang
- 1 Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Dong-Jun Lv
- 1 Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China.,2 Institute of Neuroscience, Soochow University, Suzhou, China
| | - Ya-Ping Yang
- 1 Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Kai-Lin Xia
- 2 Institute of Neuroscience, Soochow University, Suzhou, China
| | - Jun-Yi Liu
- 2 Institute of Neuroscience, Soochow University, Suzhou, China
| | - Fen Wang
- 2 Institute of Neuroscience, Soochow University, Suzhou, China
| | - Li-Fang Hu
- 2 Institute of Neuroscience, Soochow University, Suzhou, China
| | - Guang-Yin Xu
- 2 Institute of Neuroscience, Soochow University, Suzhou, China
| | - Chun-Feng Liu
- 1 Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China.,2 Institute of Neuroscience, Soochow University, Suzhou, China
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47
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Lima LV, DeSantana JM, Rasmussen LA, Sluka KA. Short-duration physical activity prevents the development of activity-induced hyperalgesia through opioid and serotoninergic mechanisms. Pain 2017; 158:1697-1710. [PMID: 28621702 PMCID: PMC5561491 DOI: 10.1097/j.pain.0000000000000967] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Regular physical activity prevents the development of chronic muscle pain through the modulation of central mechanisms that involve rostral ventromedial medulla (RVM). We tested if pharmacological blockade or genetic deletion of mu-opioid receptors in physically active mice modulates excitatory and inhibitory systems in the RVM in an activity-induced hyperalgesia model. We examined response frequency to mechanical stimulation of the paw, muscle withdrawal thresholds, and expression of phosphorylation of the NR1 subunit of the N-methyl-D-aspartate receptor (p-NR1) and serotonin transporter (SERT) in the RVM. Mice that had performed 5 days of voluntary wheel running prior to the induction of the model were compared with sedentary mice. Sedentary mice showed significant increases in mechanical paw withdrawal frequency and a reduction in muscle withdrawal threshold; wheel running prevented the increase in paw withdrawal frequency. Naloxone-treated and MOR mice had increases in withdrawal frequency that were significantly greater than that in physically active control mice and similar to sedentary mice. Immunohistochemistry in the RVM showed increases in p-NR1 and SERT expression in sedentary mice 24 hours after the induction of the model. Wheel running prevented the increase in SERT, but not p-NR1. Physically active, naloxone-treated, and MOR mice showed significant increases in SERT immunoreactivity when compared with wild-type physically active control mice. Blockade of SERT in the RVM in sedentary mice reversed the activity-induced hyperalgesia of the paw and muscle. These results suggest that analgesia induced by 5 days of wheel running is mediated by mu-opioid receptors through the modulation of SERT, but not p-NR1, in RVM.
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MESH Headings
- Animals
- Disease Models, Animal
- Female
- Gene Expression Regulation/physiology
- Hyperalgesia/etiology
- Hyperalgesia/prevention & control
- Male
- Medulla Oblongata/metabolism
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Nerve Tissue Proteins/metabolism
- Pain Measurement
- Pain Threshold/physiology
- Physical Conditioning, Animal/methods
- Physical Stimulation/adverse effects
- Receptors, N-Methyl-D-Aspartate/metabolism
- Receptors, Opioid, mu/genetics
- Receptors, Opioid, mu/metabolism
- Serotonin Plasma Membrane Transport Proteins/metabolism
- Statistics, Nonparametric
- Time Factors
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Affiliation(s)
- Lucas V Lima
- Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, IA, USA
- Graduate Program in Health Sciences, Federal University of Sergipe, Aracaju/Se, Brazil
| | - Josimari M DeSantana
- Graduate Program in Health Sciences, Federal University of Sergipe, Aracaju/Se, Brazil
- Department of Physical Therapy, Federal University of Sergipe, Aracaju/Se, Brazil
| | - Lynn A Rasmussen
- Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, IA, USA
| | - Kathleen A Sluka
- Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, IA, USA
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48
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Central Sensitization-Based Classification for Temporomandibular Disorders: A Pathogenetic Hypothesis. Pain Res Manag 2017; 2017:5957076. [PMID: 28932132 PMCID: PMC5592418 DOI: 10.1155/2017/5957076] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 06/03/2017] [Accepted: 07/09/2017] [Indexed: 12/15/2022]
Abstract
Dysregulation of Autonomic Nervous System (ANS) and central pain pathways in temporomandibular disorders (TMD) is a growing evidence. Authors include some forms of TMD among central sensitization syndromes (CSS), a group of pathologies characterized by central morphofunctional alterations. Central Sensitization Inventory (CSI) is useful for clinical diagnosis. Clinical examination and CSI cannot identify the central site(s) affected in these diseases. Ultralow frequency transcutaneous electrical nerve stimulation (ULFTENS) is extensively used in TMD and in dental clinical practice, because of its effects on descending pain modulation pathways. The Diagnostic Criteria for TMD (DC/TMD) are the most accurate tool for diagnosis and classification of TMD. However, it includes CSI to investigate central aspects of TMD. Preliminary data on sensory ULFTENS show it is a reliable tool for the study of central and autonomic pathways in TMD. An alternative classification based on the presence of Central Sensitization and on individual response to sensory ULFTENS is proposed. TMD may be classified into 4 groups: (a) TMD with Central Sensitization ULFTENS Responders; (b) TMD with Central Sensitization ULFTENS Nonresponders; (c) TMD without Central Sensitization ULFTENS Responders; (d) TMD without Central Sensitization ULFTENS Nonresponders. This pathogenic classification of TMD may help to differentiate therapy and aetiology.
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49
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Discovery of endogenous opioid systems: what it has meant for the clinician's understanding of pain and its treatment. Pain 2017; 158:2290-2300. [DOI: 10.1097/j.pain.0000000000001043] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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50
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Tian Z, Yamanaka M, Bernabucci M, Zhao MG, Zhuo M. Characterization of serotonin-induced inhibition of excitatory synaptic transmission in the anterior cingulate cortex. Mol Brain 2017; 10:21. [PMID: 28606116 PMCID: PMC5468981 DOI: 10.1186/s13041-017-0303-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 06/05/2017] [Indexed: 01/31/2023] Open
Abstract
Excitatory synaptic transmission in central synapses is modulated by serotonin (5-HT). The anterior cingulate cortex (ACC) is an important cortical region for pain perception and emotion. ACC neurons receive innervation of projecting serotonergic nerve terminals from raphe nuclei, but the possible effect of 5-HT on excitatory transmission in the ACC has not been investigated. In the present study, we investigated the role of 5-HT on glutamate neurotransmission in the ACC slices of adult mice. Bath application of 5-HT produced dose-dependent inhibition of evoked excitatory postsynaptic currents (eEPSCs). Paired pulse ratio (PPR) was significantly increased, indicating possible presynaptic effects of 5-HT. Consistently, bath application of 5-HT significantly decreased the frequency of spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs). By contrast, amplitudes of sEPSCs and mEPSCs were not significantly affected. After postsynaptic application of G protein inhibitor GDP-β-S, 5-HT produced inhibition of eEPSCs was significantly reduced. Finally, NAN-190, an antagonist of 5-HT1A receptor, significantly reduced postsynaptic inhibition of 5-HT and abolished presynaptic inhibition. Our results strongly suggest that presynaptic as well as postsynaptic 5-HT receptor including 5-HT1A subtype receptor may contribute to inhibitory modulation of glutamate release as well as postsynaptic responses in the ACC.
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Affiliation(s)
- Zhen Tian
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, Shanxi, 710049, China.,Department of Pharmacy, The 154th central hospital of PLA, Xinyang, Henan, 464000, China.,Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Manabu Yamanaka
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, Shanxi, 710049, China.,Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Matteo Bernabucci
- Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Ming-Gao Zhao
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, Shanxi, 710049, China
| | - Min Zhuo
- Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, Shanxi, 710049, China. .,Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
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