Cellular Tolerance Induced by Chronic Opioids in the Central Nervous System.
Cellular Tolerance Induced by Chronic Opioids in the Central Nervous System.
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DOI：
10.3389/fnsys.2022.937126
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发表时间：
2022
影响因子：
3
通讯作者：
Williams, John T.
中科院分区：
文献类型：
--
作者：
Adhikary, Sweta;Williams, John T.
阿片类药物是一种强效镇痛药，通过作用于阿片受体（mu opioid receptor， MOR）而引起急性抗痛觉作用。然而，阿片类药物对慢性疼痛治疗无效，部分原因是MORs的持续激活诱导了受体水平和下游信号分子的适应性变化。这些适应包括受体-效应耦合的减少和第二信使系统的变化，这些变化可以抵消阿片受体激动剂对MORs的持续激活。MORs的稳态调节和下游信号级联被认为是产生耐受性的前兆。然而，尽管许多研究确定了促成阿片类药物耐受性的关键机制，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。阿片耐受性是一个多方面的过程，既涉及含有MOR的单个神经元，也涉及在MOR连续激活后进行适应的神经元回路。最近的事件是激动剂/受体相互作用导致急性细胞作用。这篇综述讨论了我们对慢性阿片类药物治疗后介导细胞耐受的机制的理解，其中部分是由激动剂/受体急性相互作用介导的。
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.
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