Opioid-induced glial activation: mechanisms of activation and implications for opioid analgesia, dependence, and reward.
Opioid-induced glial activation: mechanisms of activation and implications for opioid analgesia, dependence, and reward.
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DOI：
10.1100/tsw.2007.230
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发表时间：
2007-11-02
影响因子：
--
通讯作者：
Watkins LR
中科院分区：
文献类型：
--
作者：
Hutchinson MR;Bland ST;Johnson KW;Rice KC;Maier SF;Watkins LR
本文将介绍Toll样受体(Toll-like Receptor，TLR)介导的神经胶质细胞激活的概念，它是神经病理性疼痛、急性阿片类药物镇痛和不良阿片类药物副作用(耐受性、依赖性和奖赏)的核心。先前已经证明，减弱神经胶质细胞的激活既可以缓解实验性疼痛模型引起的夸大疼痛状态，又可以减少阿片类药物耐受的发展。在这里，我们证明了TLR4的选择性急性拮抗导致神经病理性疼痛的逆转以及阿片类止痛的增强。减弱中枢神经系统神经胶质细胞的激活也被发现可以减少阿片类药物依赖的发展，并在行为(条件性位置偏爱)和神经化学(伏隔核微透析吗啡诱导的多巴胺升高)水平上分析阿片类药物奖励。此外，(+)-和(˗)-阿片异构体拮抗剂对TLR4的一种新的拮抗作用已被表征，并显示出抗痛觉过敏和吗啡镇痛增强活性。阿片类激动剂也被发现具有TLR4激动剂活性，预测神经胶质细胞的激活。靶向神经胶质细胞激活是一种治疗神经病理性疼痛的新方法，但在临床上尚未被开发。此外，这些数据表明，通过全面或选择性的TLR拮抗机制来减弱神经胶质细胞的激活，也可能是分离阿片类药物有益(镇痛)和有害(耐受、依赖和奖励)作用的一种临床方法，从而提高其使用的安全性和有效性。
This review will introduce the concept of toll-like receptor (TLR)–mediated glial activation as central to all of the following: neuropathic pain, compromised acute opioid analgesia, and unwanted opioid side effects (tolerance, dependence, and reward). Attenuation of glial activation has previously been demonstrated both to alleviate exaggerated pain states induced by experimental pain models and to reduce the development of opioid tolerance. Here we demonstrate that selective acute antagonism of TLR4 results in reversal of neuropathic pain as well as potentiation of opioid analgesia. Attenuating central nervous system glial activation was also found to reduce the development of opioid dependence, and opioid reward at a behavioral (conditioned place preference) and neurochemical (nucleus accumbens microdialysis of morphine-induced elevations in dopamine) level of analysis. Moreover, a novel antagonism of TLR4 by (+)- and (˗)-isomer opioid antagonists has now been characterized, and both antiallodynic and morphine analgesia potentiating activity shown. Opioid agonists were found to also possess TLR4 agonistic activity, predictive of glial activation. Targeting glial activation is a novel and as yet clinically unexploited method for treatment of neuropathic pain. Moreover, these data indicate that attenuation of glial activation, by general or selective TLR antagonistic mechanisms, may also be a clinical method for separating the beneficial (analgesia) and unwanted (tolerance, dependence, and reward) actions of opioids, thereby improving the safety and efficacy of their use.