Spinal nerve injury activates prostaglandin synthesis in the spinal cord that contributes to early maintenance of tactile allodynia

Abstract Background Peripheral nerve injury–induced gene alterations in the dorsal root ganglion (DRG) and spinal cord likely participate in neuropathic pain genesis. Histone methylation gates gene expression. Whether the suppressor of variegation 3-9 homolog 1 (SUV39H1), a histone methyltransferase, contributes to nerve injury–induced nociceptive hypersensitivity is unknown. Methods Quantitative real-time reverse transcription polymerase chain reaction analysis, Western blot analysis, or immunohistochemistry were carried out to examine the expression of SUV39H1 mRNA and protein in rat DRG and dorsal horn and its colocalization with DRG μ-opioid receptor (MOR). The effects of a SUV39H1 inhibitor (chaetocin) or SUV39H1 siRNA on fifth lumbar spinal nerve ligation (SNL)–induced DRG MOR down-regulation and nociceptive hypersensitivity were examined. Results SUV39H1 was detected in neuronal nuclei of the DRG and dorsal horn. It was distributed predominantly in small DRG neurons, in which it coexpressed with MOR. The level of SUV39H1 protein in both injured DRG and ipsilateral fifth lumbar dorsal horn was time dependently increased after SNL. SNL also produced an increase in the amount of SUV39H1 mRNA in the injured DRG (n = 6/time point). Intrathecal chaetocin or SUV39H1 siRNA as well as DRG or intraspinal microinjection of SUV39H1 siRNA impaired SNL-induced allodynia and hyperalgesia (n = 5/group/treatment). DRG microinjection of SUV39H1 siRNA also restored SNL-induced DRG MOR down-regulation (n = 6/group). Conclusions The findings of this study suggest that SUV39H1 contributes to nerve injury–induced allodynia and hyperalgesia through gating MOR expression in the injured DRG. SUV39H1 may be a potential target for the therapeutic treatment of nerve injury–induced nociceptive hypersensitivity.

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Mediation of spinal nerve injury induced tactile allodynia by descending facilitatory pathways in the dorsolateral funiculus in rats

Neuroscience Letters ◽

10.1016/s0304-3940(00)01338-0 ◽

2000 ◽

Vol 290 (2) ◽

pp. 129-132 ◽

Cited By ~ 65

Author(s):

Michael H Ossipov ◽

Hong Sun T ◽

Phil Malan ◽

Josephine Lai ◽

Frank Porreca

Keyword(s):

Nerve Injury ◽

Spinal Nerve ◽

Tactile Allodynia ◽

Dorsolateral Funiculus

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Peri-sciatic administration of indomethacin early after nerve injury can attenuate the development of tactile allodynia in a rat model of L5 single spinal nerve injury

Neuroscience Letters ◽

10.1016/j.neulet.2003.11.017 ◽

2004 ◽

Vol 356 (1) ◽

pp. 37-40 ◽

Cited By ~ 9

Author(s):

Masahiro Takahashi ◽

Masahiko Kawaguchi ◽

Keiji Shimada ◽

Noboru Konishi ◽

Hitoshi Furuya ◽

...

Keyword(s):

Nerve Injury ◽

Rat Model ◽

Spinal Nerve ◽

Tactile Allodynia

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Spinal CXCL9 and CXCL11 are not involved in neuropathic pain despite an upregulation in the spinal cord following spinal nerve injury

Molecular Pain ◽

10.1177/1744806918777401 ◽

2018 ◽

Vol 14 ◽

pp. 174480691877740 ◽

Cited By ~ 8

Author(s):

Xiao-Bo Wu ◽

Li-Na He ◽

Bao-Chun Jiang ◽

Hui Shi ◽

Xue-Qiang Bai ◽

...

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Nerve Injury ◽

Spinal Nerve

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

The Open Pain Journal ◽

10.2174/1876386301407010001 ◽

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.

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

Anesthesiology ◽

10.1097/00000542-200311000-00026 ◽

2003 ◽

Vol 99 (5) ◽

pp. 1175-1179 ◽

Cited By ~ 42

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.

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