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Intrathecal Injection of JWH015 Attenuates Remifentanil-Induced Postoperative Hyperalgesia by Inhibiting Activation of Spinal Glia in a Rat Model

Sun, Yu’e MD; Zhang, Wei MD; Liu, Yue MD; Liu, Xiaojie MD; Ma, Zhengliang PhD; Gu, Xiaoping PhD

doi: 10.1213/ANE.0000000000000146
Pain and Analgesic Mechanisms: Research Report

BACKGROUND: Hyperalgesia and neuroinflammation are associated with glia, which consists of macroglia and microglia. In this study, we used a selective cannabinoid receptor type 2 (CB2) agonist JWH015 to investigate remifentanil-induced postoperative hyperalgesia.

METHODS: Mechanical allodynia and thermal hyperalgesia after postoperative hyperalgesia and intrathecal injection of JWH015 were assessed by the paw withdrawal mechanical threshold and paw withdrawal thermal latency tests. We used immunohistochemistry and immunoblotting to investigate the effect of JWH015 on CB2 receptor, NR2B subunits, activated glial cells, and proinflammatory cytokine expression in rats after remifentanil-induced postoperative hyperalgesia.

RESULTS: Postoperative hyperalgesia was induced by intraoperative infusion of remifentanil. Glial cells were activated, and expression levels of several genes were significantly increased, including interleukin 6, tumor necrosis factor α, CB2, and the NR2B subunit phosphorylated at Tyr-1472 (p-NR2B). Intrathecal injection of JWH015 significantly inhibited glial cell activation, suppressed expression of interleukin 6, tumor necrosis factor α, and p-NR2B, and stimulated CB2 expression, thus attenuating postoperative hyperalgesia. However, these phenomena were abolished in the group that was preadministered with AM630.

CONCLUSIONS: The activation of glia, the production of proinflammatory cytokines, and the expression of CB2 and p-NR2B in the spinal dorsal horn increase significantly during the process of remifentanil-induced hyperalgesia. These changes can be regulated by pretreatment with JWH015, which may be the main mechanism underlying the antihyperalgesia effects of JWH015.

From the Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical College of Nanjing University, Nanjing, Jiangsu province, China.

Accepted for publication January 15, 2014.

Funding: This research was supported by National Natural Foundation of China (81171047/H0903, 81070892, 81171048, 81371207, 81300950, 81300951) and National Natural Foundation of Jiangsu Province, China (BK2010105, 2010117, RC2011006, XK201140), Medical Technology Development Funds of Nanjing, China (YKK13068) and Youth Foundation of drum-tower hospital (QJ2012011).

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Xiaoping Gu, PhD, and Zhengliang Ma, PhD, Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical College of Nanjing University, NO 321 Zhongshan Rd., Nanjing, Jiangsu Province. Address e-mail to;

© 2014 International Anesthesia Research Society