Cannabinoid subtype-2 receptors modulate the antihyperalgesic effect of WIN 55,212-2 in rats with neuropathic spinal cord injury pain
Cannabinoid subtype-2 receptors modulate the antihyperalgesic effect of WIN 55,212-2 in rats with neuropathic spinal cord injury pain
复制标题
DOI：
10.1016/j.spinee.2010.08.015
复制
发表时间：
2010-12-01
期刊：
影响因子：
4.5
通讯作者：
Resnick, Daniel K.
中科院分区：
文献类型：
--
作者：
Ahmed, Mostafa M.;Rajpal, Sharad;Resnick, Daniel K.
背景：越来越多的证据表明，大麻素(CB)系统在脊髓损伤(SCI)后神经病理性疼痛(NP)的发生中发挥了作用。非特异性CB1和CB2受体激动剂Win 55,212-2(Win)先前已被证明可以减轻周围神经损伤后的机械性和热性痛敏(TH)。PURPOSE：本研究旨在通过选择性CB1和CB2受体拮抗剂来确定参与WIN抗痛敏作用的CB受体。研究设计：这是一项使用中度T9挫伤脊髓损伤的体内和行为学研究。方法：采用多中心动物脊髓损伤研究(Mascis)减重冲击法造成大鼠脊髓挫伤，造成中度T9脊髓损伤。只有脚底踏步一致、前肢和后肢协调一致的动物(Basso、Beattie和Bresna han评分=15)才被测试TH。在第42天或之前，表现出戒断潜伏期缩短的动物被选为药物干预组。没有表现出TH的动物没有接受药物干预，并被处死。在给药前(伤后)、选择性CB拮抗剂(AM 251或AM 630)给药后45min(拮抗剂后)和WIN给药后45min(WIN后)，对大鼠进行后爪测试。共7个治疗组：生理盐水对照组、二甲基亚砜(DMSO)载体对照组、低剂量温和温(0.2 mg/kg)组、高剂量温和温(2.0 mg/kg)组、黄芪251(3 mg/kg)、黄芪630(1 mg/kg)皮下注射，总体积0.5mL。结果：给药组大鼠热痛敏明显改善，且呈剂量依赖关系。大麻素1型受体拮抗剂AM 251预处理不影响Win的止痛作用。相反，CB2受体拮抗剂AM 630可显著减弱WIN的作用。结论：以上结果提示，CB2受体在脊髓损伤后TH的调节中起一定作用。选择性激活CB2受体可潜在地对脊髓损伤患者产生止痛作用，同时避免精神药物副作用。(C)2010 Elsevier Inc.保留所有权利。
BACKGROUND CONTEXT: There is increasing evidence for a role of the cannabinoid (CB) system in the development of neuropathic pain (NP) after spinal cord injury (SCI). The nonspecific CB1 and CB2 receptor agonists, WIN 55, 212-2 (WIN), have previously been shown to alleviate both mechanical and thermal hyperalgesia (TH) after peripheral nerve injury.PURPOSE: The present study was designed to identify the CB receptors involved in the antihyperalgesic effect of WIN by using selective antagonists for CB1 and CB2 receptors.STUDY DESIGN: This is an in vivo and behavioral study using a moderate T9 contusion SCI. After injury, TH of the hind paws was measured on postinjury days 21 through 42.METHODS: Sprague-Dawley rats underwent a contusion SCI using the Multicenter Animal Spinal Cord Injury Study (MASCIS) weight-drop impactor, which induced a moderate T9 SCI. Only animals showing consistent plantar stepping and consistent forelimb and hind limb coordination (Basso, Beattie, and Bresnahan score=15) were tested for TH. Animals exhibiting decreased withdrawal latency time, indicating TH, on or before Day 42, were selected for pharmacological intervention. Animals not exhibiting TH did not receive pharmacological intervention and were sacrificed. Rats underwent hind paw testing before any drug administration (after injury), 45 minutes after selective CB antagonist (AM 251 or AM 630) administration (postantagonist) and again 45 minutes after WIN administration (post-WIN). There were a total of seven treatment groups: saline vehicle control; Dimethyl sulfoxide (DMSO) vehicle control; low-dose WIN (0.2 mg/kg); and high-dose WIN (2.0 mg/kg); AM 251 (3 mg/kg) and AM 630 (1 mg/kg) were given subcutaneously in a total volume of 0.5 mL. Followed by intraperitoneal injection of WIN after each antagonist, sham-operated rats repeated pharmacological intervention used with treatment Groups 5 and 6.RESULTS: Thermal hyperalgesia was significantly ameliorated in a dose-dependent manner with systemically administered WIN. Cannabinoid receptor Type 1 antagonist AM 251 pretreatment did not affect the antihyperalgesic effect of WIN. By contrast, pretreatment with the CB2 receptor antagonist AM 630 significantly attenuated the effect of WIN.CONCLUSION: Taken together, these results suggest a role of the CB2 receptor in modulating SCI-induced TH. Selective activation of the CB2 receptor could potentially lead to analgesic effects on NP while avoiding psychotropic side effects in patients with SCI. (C) 2010 Elsevier Inc. All rights reserved.