Pathological pain is regulated by a balance between pro-algesic and analgesic mechanisms. Interactions between opioid peptide-producing immune cells and peripheral sensory neurons expressing opioid receptors represent a powerful intrinsic pain control in animal models and in humans. Therefore, treatments based on general suppression of immune responses have been mostly unsuccessful. It is highly desirable to develop strategies that specifically promote neuro-immune communication mediated by opioids. Promising examples include vaccination-based recruitment of opioid-containing leukocytes to painful tissue and the local reprogramming of pro-algesic immune cells into analgesic cells producing and secreting high amounts of opioid peptides. Such approaches have the potential to inhibit pain at its origin and be devoid of central and systemic side effects of classical analgesics. In support of these concepts, in this article, we describe the functioning of peripheral opioid receptors, migration of opioid-producing immune cells to inflamed tissue, opioid peptide release, and the consequent pain relief. Conclusively, we provide clinical evidence and discuss therapeutic opportunities and challenges associated with immune cell-mediated peripheral opioid analgesia.

病理性疼痛受促镇痛和镇痛机制之间的平衡调节。产生阿片肽的免疫细胞与表达阿片受体的外周感觉神经元之间的相互作用代表了动物模型和人类强大的内在疼痛控制。因此，基于免疫反应的一般抑制的治疗大多不成功。非常需要制定专门促进由阿片类药物介导的神经免疫交流的策略。有希望的例子包括基于疫苗接种的含阿片类药物的白细胞募集到疼痛组织，以及将促镇痛免疫细胞局部重编程为镇痛细胞，产生和分泌大量阿片类肽。这种方法有可能从根源上抑制疼痛，并且没有经典镇痛药的中枢和全身副作用。为了支持这些概念，在本文中，我们描述了外周阿片受体的功能、产生阿片的免疫细胞向发炎组织的迁移、阿片肽的释放以及随之而来的疼痛缓解。最后，我们提供临床证据并讨论与免疫细胞介导的外周阿片类镇痛相关的治疗机会和挑战。