University of Wisconsin School of Medicine and Public Health, Madison, WI 53595, USA.
Pain Physician. 2011 May-Jun;14(3):249-58.
Opioid receptors are widely expressed in the central and peripheral nervous system and in the non-neuronal tissues. Data from animal and human clinical studies support the involvement of peripheral opioid receptors in analgesia, especially in the presence of inflammation. Inflammation has been shown to increase the synthesis of opioid receptors in the dorsal root ganglion neurons and enhance transport and accumulation of opioid receptors in the peripheral terminals of sensory neurons. Under the influence of chemokines and adhesion molecules, opioid peptide-containing immune cells extravasate and accumulate in the injured tissues. Stress, chemokines, cytokines, and other releasing factors in inflamed tissues stimulate these granulocytes to release opioid peptides. Once secreted, opioid peptides bind to and activate peripheral opioid receptors on sensory nerve fibers and produce analgesia by decreasing the excitability of sensory nerves and/or inhibiting release of pro-inflammatory neuropeptides. Research has revealed that local application of exogenous opioid agonists produces a potent analgesic effect by activating peripheral opioid receptors in inflamed tissues. The analgesic activity occurs without activation of opioid receptors in the central nervous system (CNS), and therefore centrally mediated side effects, such as respiratory depression, mental clouding, altered consciousness, or addiction, are not associated with peripheral opioid activity. This discovery has stimulated research on developing peripherally restricted opioid agonists that lack CNS effects. In addition, it has been recognized that opioid receptors modulate inflammation, and that opioids have anti-inflammatory effects. The anti-inflammatory actions of opioids are not well known or understood. Conflicting reports on mu-opioids suggest both anti-inflammatory and pro-inflammatory effects. This article will present the basis for peripheral opioid analgesia and describe current research directed at developing novel treatments for pain with improved side effect profiles.
阿片受体广泛表达于中枢和外周神经系统以及非神经元组织中。动物和人体临床研究数据支持外周阿片受体在镇痛中的作用，尤其是在存在炎症的情况下。研究表明，炎症会增加背根神经节神经元中阿片受体的合成，并增强感觉神经元外周末端阿片受体的转运和积累。在趋化因子和黏附分子的影响下，含有阿片肽的免疫细胞渗出并积聚在受损组织中。炎症组织中的应激、趋化因子、细胞因子和其他释放因子刺激这些粒细胞释放阿片肽。一旦分泌，阿片肽与感觉神经纤维上的外周阿片受体结合并激活，通过降低感觉神经的兴奋性和/或抑制促炎神经肽的释放来产生镇痛作用。研究表明，局部应用外源性阿片激动剂通过激活炎症组织中的外周阿片受体产生强大的镇痛作用。这种镇痛活性不会激活中枢神经系统（CNS）中的阿片受体，因此不会产生与外周阿片活性相关的中枢介导的副作用，如呼吸抑制、精神模糊、意识改变或成瘾。这一发现激发了研究开发缺乏 CNS 作用的外周限制阿片激动剂。此外，人们已经认识到阿片受体可以调节炎症，并且阿片类药物具有抗炎作用。阿片类药物的抗炎作用还不太清楚或理解。关于μ阿片类药物的相互矛盾的报告表明既有抗炎作用又有促炎作用。本文将介绍外周阿片类镇痛的基础，并描述目前针对疼痛治疗的研究进展，以改善副作用谱。
