Adhikary Sweta, Williams John T
Vollum Institute, Oregon Health & Science University, Portland, OR, United States.
Front Syst Neurosci. 2022 Jun 28;16:937126. doi: 10.3389/fnsys.2022.937126. eCollection 2022.
Opioids are powerful analgesics that elicit acute antinociceptive effects through their action the mu opioid receptor (MOR). However opioids are ineffective for chronic pain management, in part because continuous activation of MORs induces adaptive changes at the receptor level and downstream signaling molecules. These adaptations include a decrease in receptor-effector coupling and changes to second messenger systems that can counteract the persistent activation of MORs by opioid agonists. Homeostatic regulation of MORs and downstream signaling cascades are viewed as precursors to developing tolerance. However, despite numerous studies identifying crucial mechanisms that contribute to opioid tolerance, no single regulatory mechanism that governs tolerance in at the cellular and systems level has been identified. Opioid tolerance is a multifaceted process that involves both individual neurons that contain MORs and neuronal circuits that undergo adaptations following continuous MOR activation. The most proximal event is the agonist/receptor interaction leading to acute cellular actions. This review discusses our understanding of mechanisms that mediate cellular tolerance after chronic opioid treatment that, in part, is mediated by agonist/receptor interaction acutely.
阿片类药物是强效镇痛药，通过作用于μ阿片受体（MOR）产生急性抗伤害感受作用。然而，阿片类药物对慢性疼痛管理无效，部分原因是MOR的持续激活会在受体水平和下游信号分子上诱导适应性变化。这些适应性变化包括受体 - 效应器偶联的减少以及第二信使系统的改变，这些改变可以抵消阿片类激动剂对MOR的持续激活。MOR和下游信号级联的稳态调节被视为产生耐受性的前兆。然而，尽管有大量研究确定了导致阿片类耐受性的关键机制，但尚未确定在细胞和系统水平上控制耐受性的单一调节机制。阿片类耐受性是一个多方面的过程，涉及含有MOR的单个神经元以及在MOR持续激活后发生适应性变化的神经回路。最直接的事件是激动剂/受体相互作用导致急性细胞作用。本综述讨论了我们对慢性阿片类药物治疗后介导细胞耐受性机制的理解，部分是由激动剂/受体急性相互作用介导的。
