scholarly journals Spinal Cord is the Primary Site of Action of the Cannabinoid CB2 Receptor Agonist JWH133 that Suppresses Neuropathic Pain: Possible Involvement of Microglia

2014 ◽  
Vol 7 (1) ◽  
pp. 1-8
Author(s):  
Hiroshi Shimoyama ◽  
Makoto Tsuda ◽  
Takahiro Masuda ◽  
Ryohei Yoshinaga ◽  
Keiko Tsukamoto ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Nerve Injury ◽  
Intrathecal Administration ◽  
Tactile Allodynia ◽  
Cb2 Receptor ◽  
Analgesic Agents ◽  
Inflammatory Drugs ◽  
Antiallodynic Effect

Neuropathic pain, a highly debilitating condition that commonly occurs after damage to the nervous system, is often resistant to commonly used analgesic agents such as non-steroidal anti-inflammatory drugs and even opioids.Several studies using rodent models reported that cannabinoid CB2 receptor (CB2R) agonists are effective for treating chronic pain. However, the analgesic mechanism of CB2R agonists in neuropathic pain states is not fully understood. In this study, we investigated the role of CB2Rs in the development and maintenance phases of neuropathic pain, and the mechanism of the CB2R-mediated analgesic effect on neuropathic pain. In a rat model of neuropathic pain, systemic administration of JWH133, a CB2R agonist, markedly improved tactile allodynia, and this effect was prevented by intrathecal pretreatment with AM630, a CB2R antagonist. The antiallodynic effect of intrathecally administered JWH133 was inhibited by intrathecal pretreatment with pertussis toxin or forskolin. In the spinal cord, CB2R expression was significantly increased on post-operative day 3, and persisted for 2 weeks. Furthermore, repeated intrathecal administration of JWH133 notably attenuated the development of tactile allodynia after peripheral nerve injury. In a culture of microglia activated by overexpressing interferon regulatory factor 8, a transcription factor crucial for neuropathic pain, JWH133 treatment suppressed the increased expression of interleukin-1β. Our findings suggest that activation of CB2Rs upregulated in the spinal cord after nerve injury alleviates existing tactile allodynia through the Gi/oadenylate cyclase signaling pathway and suppresses the development of allodynia. This process may reduce the inflammatory response of microglia. Therefore, spinal CB2Rs may be a therapeutic target for the treatment of neuropathic pain.

CB2/miR-124 signaling down-regulate the expression of purinergic P2X4 and P2X7 receptor in dorsal spinal cord of CCI rats

2020 ◽  
Author(s):  
Rui Xu ◽  
Fan Yang ◽  
Lijuan Li ◽  
Xiaohong Liu ◽  
Xiaolu Lei ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Nerve Injury ◽  
Intrathecal Injection ◽  
Receptor Activation ◽  
Cb2 Receptor ◽  
Dorsal Spinal Cord ◽  
P38mapk Pathway ◽  
Dorsal Spinal

Abstract Background: The importance of P2X purinoceptors, CB2 receptor and microRNA-124(miR-124) in spinal cord microglia to the development of neuropathic pain was demonstrated in numerous previous studies. The upregulation of P2X4 and P2X7 receptors in spinal dorsal horn microglia is involved in the development of pain behavior caused by peripheral nerve injury. However, it is not clear whether the expression of P2X4 and P2X7 receptors at dorsal spinal cord will be influenced by CB2 receptor or miR-124 in rats after chronic sciatic nerve injury.Methods: Chronic constriction injury (CCI) of the sciatic nerve was performed in rats to induce neuropathic pain. Tests of the mechanical withdrawal threshold (MWT) were carried out to assess the response of the paw to mechanical stimulus. The expression of miR-124, P2X4, P2X7 and CB2 receptor were detected with RT-PCR. The protein expression of P2X4, P2X7 and CB2 receptor, RhoA, ROCK1, ROCK2, p-p38MAPK and p-NF-kappaBp65 was detected with Western blotting analysis. Results: Intrathecal administration of CB2 receptor agonist AM1241 significantly attenuated CCI-induced mechanical allodynia and significantly inhibited the increased expression of P2X4 and P2X7 receptors at the mRNA and protein levels, which imply that P2X4 and P2X7 receptors expression are down-regulated by AM1241 in CCI rats. Western blot analysis showed that AM1241 suppressed the elevated expression of RhoA, ROCK1, ROCK2, p-p38MAPK and NF-κBp65 in the dorsal spinal cord induced by CCI. After administration with Y-27632 (ROCK inhibitor), SB203580 (P38MAPK inhibitor) or PDTC (NF-κB inhibitor), the levels of P2X4 and P2X7 receptors expression in the dorsal spinal cord were lower than those in CCI rats, which imply that the ROCK/P38MAPK pathway and NF-κB activation may contribute to the increased expression of P2X4 and P2X7 receptor. On the other hand, in CCI rats, AM1241 treatment evoked the increased expression of CB2 receptor and miRNA-124, which can be inhibited by intrathecal injection of CB2 receptor antagonist AM630, which indicate that the increased expression of miRNA-124 may be medicated by CB2 receptor activation. In addition, the increased expression of P2X4 and P2X7 receptors in the dorsal spinal cord of CCI rats were inhibited by miRNA-124 agomir. Furthermore, intrathecal injection of miRNA-124 agomir could efficiently inhibit the ROCK/P38MAPK pathway and NF-κB activation in CCI rats. Moreover, AM1241 treatment significantly inhibited the expression of P2X4 and P2X7 receptors, and this suppression is enhanced by pretreatment with miRNA-124 agomir. On the contrast, the inhibitory effect of AM1241 on the expression of P2X4 and P2X7 receptor can be reversed by pretreatment with miRNA-124 antagomir.Conclusions: In CCI rats, intrathecal injection of AM1241 could efficiently induce the increased expression of miRNA-124, while inhibiting the ROCK/P38MAPK pathway and NF-κB activation in dorsal spinal cord. CB2 receptor/miRNA-124 signaling induced the decreased P2X4 and P2X7 receptors expression via inhibit the ROCK/P38MAPK pathway and NF-κB activation.

Increase of interleukin-6 mRNA in the spinal cord following peripheral nerve injury in the rat: potential role of IL-6 in neuropathic pain

1998 ◽  
Vol 62 (2) ◽  
pp. 228-235 ◽  
Author(s):  
Janice L Arruda ◽  
Raymond W Colburn ◽  
Amy J Rickman ◽  
Maria D Rutkowski ◽  
Joyce A DeLeo
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Interleukin 6 ◽  
Peripheral Nerve Injury ◽  
Potential Role

scholarly journals Intrathecal IGF2 siRNA injection provides long-lasting anti-allodynic effect in a spared nerve injury rat model of neuropathic pain

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0260887
Author(s):  
Wei-Hung Chan ◽  
Nian-Cih Huang ◽  
Yi-Wen Lin ◽  
Feng-Yen Lin ◽  
Chien-Sung Tsai ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Protein Expression ◽  
Nerve Injury ◽  
Quantitative Polymerase Chain Reaction ◽  
Response Duration ◽  
Intrathecal Administration ◽  
Significant Inhibition ◽  
Spared Nerve Injury ◽  
Withdrawal Threshold

Previous studies have shown an increase of insulin-like growth factor-2 (IGF2) in animal models of neuropathic pain. We aimed to examine the hypothesis that reducing the expression of IGF2 using intrathecal IGF2 small-interfering RNA (siRNA) would attenuate the development of neuropathic pain in rats after spared nerve injury (SNI). Male Wistar rats were divided into three groups: sham-operated group, in which surgery was performed to cut the muscles without injuring the nerves; SNI group, in which SNI surgery was performed to sever the nerves; and SNI + siRNA IGF2 group, in which SNI surgery was performed, and IGF2-siRNA was administered intrathecally 1 day after SNI. The rats were assessed for mechanical allodynia and cold allodynia 1 day before surgery (baseline), and at 2, 4, 6, 8, and 10 days after siRNA treatment. The rat spinal cord was collected for quantitative polymerase chain reaction and western blot analysis. Compared with the SNI group, rats that received IGF2 siRNA showed a significantly increased SNI-induced paw-withdrawal threshold to metal filament stimulation from Day 4 to Day 10 after SNI surgery. IGF2 siRNA significantly decreased the response duration from the acetone test from Day 2 to Day 10 following SNI surgery. SNI increased IGF2 mRNA expression on Day 2 and increased IGF2 protein expression on Day 8 and Day 10 in the spinal cord of the SNI rats. However, the above-mentioned effects of IGF2 mRNA and protein expression were significantly inhibited in the SNI + IGF2 siRNA group. We demonstrated that intrathecal administration of IGF2 siRNA provided significant inhibition of SNI-induced neuropathic pain via inhibition of IGF2 expression in the spinal cord. The analgesic effect lasted for 10 days. Further exploration of intrathecal IGF2 siRNA administration as a potential therapeutic strategy for neuropathic pain is warranted.

Cyclooxygenase-1 in the Spinal Cord Is Altered after Peripheral Nerve Injury

2003 ◽  
Vol 99 (5) ◽  
pp. 1175-1179 ◽  
Author(s):  
Xiaoying Zhu ◽  
James C. Eisenach
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Nerve Injury ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Male Rats ◽  
Dependent Manner ◽  
Cyclooxygenase 1 ◽  
Cox 1

Background The mechanisms underlying neuropathic pain are incompletely understood and its treatment is often unsatisfactory. Spinal cyclooxygenase-2 (COX-2) expression is upregulated after peripheral inflammation, associated with spinal prostaglandin production leading to central sensitization, but the role of COX isoenzymes in sensitization after nerve injury is less well characterized. The current study was undertaken to determine whether COX-1 was altered in this model. Methods Male rats underwent partial sciatic nerve transsection (PSNT) or L5-L6 spinal nerve ligation (SNL). Four weeks after PSNT and 4 h, 4 days, or 2 weeks after SNL, COX-1 immunohistochemistry was performed on the L2-S2 spinal cord. Results COX-1 immunoreactivity (COX-1-IR) was unaffected 4 h after SNL. In contrast, 4 days after SNL, the number of COX-1-IR cells increased in the ipsilateral spinal cord. COX-1-IR increased in cells with glial morphology in the superficial laminae, but decreased in the rest of the ipsilateral spinal cord 4 weeks after PSNT and 2 weeks after SNL. These changes in immunostaining were greatest at the L5 level. Conclusion These data suggest that COX-1 expression in the spinal cord is not static, but changes in a time- and laminar-dependent manner after nerve injury. These anatomic data are consistent with observations by others that spinally administered specific COX-1 inhibitors may be useful to prevent and treat neuropathic pain.

scholarly journals SUR1, newly expressed in astrocytes, mediates neuropathic pain in a mouse model of peripheral nerve injury

2021 ◽  
Vol 17 ◽  
pp. 174480692110066
Author(s):  
Orest Tsymbalyuk ◽  
Volodymyr Gerzanich ◽  
Aaida Mumtaz ◽  
Sanketh Andhavarapu ◽  
Svetlana Ivanova ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Peripheral Nerve ◽  
Dorsal Horn ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Thermal Sensitivity ◽  
Gradual Improvement ◽  
Pain Behaviors

Background Neuropathic pain following peripheral nerve injury (PNI) is linked to neuroinflammation in the spinal cord marked by astrocyte activation and upregulation of interleukin 6 (IL -6 ), chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-X-C motif) ligand 1 (CXCL1), with inhibition of each individually being beneficial in pain models. Methods Wild type (WT) mice and mice with global or pGfap-cre- or pGFAP-cre/ERT2-driven Abcc8/SUR1 deletion or global Trpm4 deletion underwent unilateral sciatic nerve cuffing. WT mice received prophylactic (starting on post-operative day [pod]-0) or therapeutic (starting on pod-21) administration of the SUR1 antagonist, glibenclamide (10 µg IP) daily. We measured mechanical and thermal sensitivity using von Frey filaments and an automated Hargreaves method. Spinal cord tissues were evaluated for SUR1-TRPM4, IL-6, CCL2 and CXCL1. Results Sciatic nerve cuffing in WT mice resulted in pain behaviors (mechanical allodynia, thermal hyperalgesia) and newly upregulated SUR1-TRPM4 in dorsal horn astrocytes. Global and pGfap-cre-driven Abcc8 deletion and global Trpm4 deletion prevented development of pain behaviors. In mice with Abcc8 deletion regulated by pGFAP-cre/ERT2, after pain behaviors were established, delayed silencing of Abcc8 by tamoxifen resulted in gradual improvement over the next 14 days. After PNI, leakage of the blood-spinal barrier allowed entry of glibenclamide into the affected dorsal horn. Daily repeated administration of glibenclamide, both prophylactically and after allodynia was established, prevented or reduced allodynia. The salutary effects of glibenclamide on pain behaviors correlated with reduced expression of IL-6, CCL2 and CXCL1 by dorsal horn astrocytes. Conclusion SUR1-TRPM4 may represent a novel non-addicting target for neuropathic pain.

scholarly journals Role of the immune system in neuropathic pain

2019 ◽  
Vol 20 (1) ◽  
pp. 33-37 ◽  
Author(s):  
Marzia Malcangio
Keyword(s):  
Spinal Cord ◽  
Chronic Pain ◽  
Nervous System ◽  
Neuropathic Pain ◽  
Immune System ◽  
Peripheral Nerve ◽  
Dorsal Horn ◽  
Nerve Injury ◽  
Immune Cells ◽  
Peripheral Nerve Injury

AbstractBackgroundAcute pain is a warning mechanism that exists to prevent tissue damage, however pain can outlast its protective purpose and persist beyond injury, becoming chronic. Chronic Pain is maladaptive and needs addressing as available medicines are only partially effective and cause severe side effects. There are profound differences between acute and chronic pain. Dramatic changes occur in both peripheral and central pathways resulting in the pain system being sensitised, thereby leading to exaggerated responses to noxious stimuli (hyperalgesia) and responses to non-noxious stimuli (allodynia).Critical role for immune system cells in chronic painPreclinical models of neuropathic pain provide evidence for a critical mechanistic role for immune cells in the chronicity of pain. Importantly, human imaging studies are consistent with preclinical findings, with glial activation evident in the brain of patients experiencing chronic pain. Indeed, immune cells are no longer considered to be passive bystanders in the nervous system; a consensus is emerging that, through their communication with neurons, they can both propagate and maintain disease states, including neuropathic pain. The focus of this review is on the plastic changes that occur under neuropathic pain conditions at the site of nerve injury, the dorsal root ganglia (DRG) and the dorsal horn of the spinal cord. At these sites both endothelial damage and increased neuronal activity result in recruitment of monocytes/macrophages (peripherally) and activation of microglia (centrally), which release mediators that lead to sensitisation of neurons thereby enabling positive feedback that sustains chronic pain.Immune system reactions to peripheral nerve injuriesAt the site of peripheral nerve injury following chemotherapy treatment for cancer for example, the occurrence of endothelial activation results in recruitment of CX3C chemokine receptor 1 (CX3CR1)-expressing monocytes/macrophages, which sensitise nociceptive neurons through the release of reactive oxygen species (ROS) that activate transient receptor potential ankyrin 1 (TRPA1) channels to evoke a pain response. In the DRG, neuro-immune cross talk following peripheral nerve injury is accomplished through the release of extracellular vesicles by neurons, which are engulfed by nearby macrophages. These vesicles deliver several determinants including microRNAs (miRs), with the potential to afford long-term alterations in macrophages that impact pain mechanisms. On one hand the delivery of neuron-derived miR-21 to macrophages for example, polarises these cells towards a pro-inflammatory/pro-nociceptive phenotype; on the other hand, silencing miR-21 expression in sensory neurons prevents both development of neuropathic allodynia and recruitment of macrophages in the DRG.Immune system mechanisms in the central nervous systemIn the dorsal horn of the spinal cord, growing evidence over the last two decades has delineated signalling pathways that mediate neuron-microglia communication such as P2X4/BDNF/GABAA, P2X7/Cathepsin S/Fractalkine/CX3CR1, and CSF-1/CSF-1R/DAP12 pathway-dependent mechanisms.Conclusions and implicationsDefinition of the modalities by which neuron and immune cells communicate at different locations of the pain pathway under neuropathic pain states constitutes innovative biology that takes the pain field in a different direction and provides opportunities for novel approaches for the treatment of chronic pain.

Role of reactive oxygen species and spinal cord apoptotic genes in the development of neuropathic pain

2007 ◽  
Vol 55 (2) ◽  
pp. 158-166 ◽  
Author(s):  
D SINISCALCO ◽  
C FUCCIO ◽  
C GIORDANO ◽  
F FERRARACCIO ◽  
E PALAZZO ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Spinal Cord ◽  
Neuropathic Pain ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Apoptotic Genes

scholarly journals Role of Neuregulin-1/ErbB Signaling in Stem Cell Therapy for Spinal Cord Injury-Induced Chronic Neuropathic Pain

Stem Cells ◽  
2012 ◽  
Vol 31 (1) ◽  
pp. 83-91 ◽  
Author(s):  
Feng Tao ◽  
Qun Li ◽  
Su Liu ◽  
Haiying Wu ◽  
John Skinner ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Neuropathic Pain ◽  
Stem Cell ◽  
Cell Therapy ◽  
Chronic Neuropathic Pain ◽  
Neuregulin 1 ◽  
Cord Injury ◽  
Erbb Signaling

scholarly journals Sensory Neurons, Ion Channels, Inflammation and the Onset of Neuropathic Pain

2012 ◽  
Vol 39 (4) ◽  
pp. 416-435 ◽  
Author(s):  
Patrick L. Stemkowski ◽  
Peter A. Smith
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Peripheral Neuropathy ◽  
Pain Management ◽  
Sensory Neurons ◽  
Inflammatory Mediators ◽  
Primary Afferents ◽  
Ectopic Activity ◽  
Management Procedures

Neuropathic pain often fails to respond to conventional pain management procedures. here we review the aetiology of neuropathic pain as would result from peripheral neuropathy or injury. We show that inflammatory mediators released from damaged nerves and tissue are responsible for triggering ectopic activity in primary afferents and that this, in turn, provokes increased spinal cord activity and the development of ‘central sensitization’. Although evidence is mounting to support the role of interleukin-1β, prostaglandins and other cytokines in the onset of neuropathic pain, the clinical efficacy of drugs which antagonize or prevent the actions of these mediators is yet to be determined. basic science findings do, however, support the use of pre-emptive analgesia during procedures which involve nerve manipulation and the use of anti-inflammatory steroids as soon as possible following traumatic nerve injury.

Sign in / Sign up

Export Citation Format

Share Document