Opioid dose escalation to effectively control pain is often linked to the current prescription opioid abuse epidemic. This creates social as well as medical imperatives to better understand the mechanistic underpinnings of opioid tolerance to develop interventions that minimize it, thereby maximizing the analgesic effectiveness of opioids. Profound opioid analgesic tolerance can be observed in the absence of mu-opioid receptor (MOR) downregulation, aggregate MOR G protein uncoupling, and MOR desensitization, in the absence of impaired G protein coupled receptor kinase phosphorylation, arrestin binding, or endocytosis. Thus, we have explored alternative biochemical sequelae that might better account for opioid analgesic tolerance. Our findings indicate that substantial plasticity among upstream and downstream components of opioid receptor signaling and the emergence of alternative signaling pathways are major contributors to opioid analgesic tolerance. An exemplar of this plasticity is our findings that chronic morphine upregulates the MOR variants MOR-1B2 and MOR-1C1 and phosphorylation of their C-terminal sites not present in MOR-1, events causally associated with the chronic morphine-induced shift in MOR G protein coupling from predominantly G_i/G_o inhibitory to G_s-stimulatory adenylyl cyclase signaling. The unique feature(s) of these variants that underlies their susceptibility to adapting to chronic morphine by altering the nature of their G protein coupling reveals the richness and pliability of MOR signaling that is enabled by generating a wide diversity of MOR variants. Furthermore, given differential anatomical expression patterns of MOR variants, MOR splice variant-dependent adaptations to chronic morphine could enable mechanistic underpinnings of tolerance and dependence that are CNS region- and cell-specific.

为有效控制疼痛而增加阿片类药物剂量通常与当前处方阿片类药物滥用流行有关。这产生了社会和医疗需求，以更好地了解阿片类药物耐受性的机制基础，以制定将其最小化的干预措施，从而最大限度地提高阿片类药物的镇痛效果。在没有 μ-阿片受体 (MOR) 下调、聚合 MOR G 蛋白解偶联和 MOR 脱敏的情况下，在没有受损的 G 蛋白偶联受体激酶磷酸化、抑制素结合或内吞作用的情况下，可以观察到深刻的阿片类镇痛耐受性。因此，我们探索了可能更好地解释阿片类镇痛耐受性的替代生化后遗症。我们的研究结果表明，阿片受体信号的上游和下游成分之间的实质性可塑性以及替代信号通路的出现是阿片类镇痛耐受的主要因素。这种可塑性的一个例子是我们的发现，即慢性吗啡上调 MOR 变体 MOR-1B2 和 MOR-1C1 及其 C 末端位点的磷酸化，而 MOR-1 中不存在，这些事件与慢性吗啡诱导的 MOR G 转变有因果关系主要来自 G 的蛋白质偶联_i/ G _o抑制 G _{s -}刺激性腺苷酸环化酶信号传导。这些变体的独特特征是通过改变其 G 蛋白偶联的性质来适应慢性吗啡的易感性，揭示了 MOR 信号的丰富性和柔韧性，这是通过产生广泛多样的 MOR 变体实现的。此外，考虑到 MOR 变体的不同解剖表达模式，MOR 剪接变体依赖性对慢性吗啡的适应可以实现中枢神经系统区域和细胞特异性的耐受性和依赖性的机制基础。