Endogenous opioid peptides and prescription opioid drugs modulate pain, anxiety and stress by activating four opioid receptors, namely μ (mu, MOP), δ (delta, DOP), κ (kappa, KOP) and the nociceptin/orphanin FQ receptor (NOP). Interestingly, several other receptors are also activated by endogenous opioid peptides and influence opioid-driven signaling and biology. However, they do not meet the criteria to be recognized as classical opioid receptors, as they are phylogenetically distant from them and are insensitive to classical non-selective opioid receptor antagonists (e.g. naloxone). Nevertheless, accumulating reports suggest that these receptors may be interesting alternative targets, especially for the development of safer analgesics. Five of these opioid peptide-binding receptors belong to the family of G protein-coupled receptors (GPCRs)—two are members of the Mas-related G protein-coupled receptor X family (MrgX1, MrgX2), two of the bradykinin receptor family (B_1, B₂), and one is an atypical chemokine receptor (ACKR3). Additionally, the ion channel N-methyl-d-aspartate receptors (NMDARs) are also activated by opioid peptides. In this review, we recapitulate the implication of these alternative receptors in opioid-related disorders and discuss their unconventional biology, with members displaying signaling to scavenging properties. We provide an overview of their established and emerging roles and pharmacology in the context of pain management, as well as their clinical relevance as alternative targets to overcome the hurdles of chronic opioid use. Given the involvement of these receptors in a wide variety of functions, including inflammation, chemotaxis, anaphylaxis or synaptic transmission and plasticity, we also discuss the challenges associated with the modulation of both their canonical and opioid-driven signaling.

内源性阿片肽和处方阿片类药物通过激活四种阿片受体，即 μ (mu, MOP)、δ (delta, DOP)、κ (kappa, KOP) 和伤害感受素/孤儿啡肽 FQ 受体 (NOP) 来调节疼痛、焦虑和压力. 有趣的是，其他几种受体也被内源性阿片肽激活并影响阿片驱动的信号传导和生物学。然而，它们不符合被认为是经典阿片受体的标准，因为它们在系统发育上与它们相距甚远，并且对经典的非选择性阿片受体拮抗剂不敏感（例如. 纳洛酮）。然而，越来越多的报告表明，这些受体可能是有趣的替代靶标，尤其是对于开发更安全的镇痛药而言。这些阿片肽结合受体中有五个属于 G 蛋白偶联受体 (GPCR) 家族——两个是 Mas 相关的 G 蛋白偶联受体 X 家族 (MrgX1、MrgX2) 的成员，两个是缓激肽受体家族的成员。 B _1, B ₂ )，一种是非典型趋化因子受体 (ACKR3)。此外，离子通道 N-甲基-d-天冬氨酸受体 (NMDAR) 也被阿片肽激活。在这篇综述中，我们概括了这些替代受体在阿片类药物相关疾病中的意义，并讨论了它们的非常规生物学，其中成员显示出信号清除特性。我们概述了它们在疼痛管理方面的既定和新兴作用和药理学，以及它们作为克服慢性阿片类药物使用障碍的替代目标的临床相关性。鉴于这些受体参与多种功能，包括炎症、趋化性、过敏反应或突触传递和可塑性，我们还讨论了与调节其规范和阿片类药物驱动信号传导相关的挑战。