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

Hiroshi Shimoyama, Makoto Tsuda*, Takahiro Masuda, Ryohei Yoshinaga, Keiko Tsukamoto, Hidetoshi Tozaki-Saitoh, Kazuhide Inoue*
Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University,Fukuoka, Japan.

© 2014 Shimoyama et al .

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; Tel: +81-92-642-6628; Fax: +81-92-642-4729; E-mails: and


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.

Keywords: Allodynia, Cannabinoid CB2 Receptor, Microglia, Neuropathic Pain, Spinal Cord.