Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia

Background
A subset of the population receiving opioids for the treatment of acute and chronic clinical pain develops a paradoxical increase in pain sensitivity known as opioid-induced hyperalgesia. Given that opioid analgesics are one of few treatments available against clinical pain, it is critical to determine the key molecular mechanisms that drive opioid-induced hyperalgesia in order to reduce its prevalence. Recent evidence implicates a splice variant of the mu opioid receptor known as MOR-1K in the emergence of opioid-induced hyperalgesia. Results from human genetic association and cell signaling studies demonstrate that MOR-1K contributes to decreased opioid analgesic responses and produces increased cellular activity via Gs signaling. Here, we conducted the first study to directly test the role of MOR-1K in opioid-induced hyperalgesia.
Methods and Results
In order to examine the role of MOR-1K in opioid-induced hyperalgesia, we first assessed pain responses to mechanical and thermal stimuli prior to, during, and following chronic morphine administration. Results show that genetically diverse mouse strains (C57BL/6J, 129S6, and CXB7/ByJ) exhibited different morphine response profiles with corresponding changes in MOR-1K gene expression patterns. The 129S6 mice exhibited an analgesic response correlating to a measured decrease in MOR-1K gene expression levels, while CXB7/ByJ mice exhibited a hyperalgesic response correlating to a measured increase in MOR-1K gene expression levels. Furthermore, knockdown of MOR-1K in CXB7/ByJ mice via chronic intrathecal siRNA administration not only prevented the development of opioid-induced hyperalgesia, but also unmasked morphine analgesia.
Conclusions
These findings suggest that MOR-1K is likely a necessary contributor to the development of opioid-induced hyperalgesia. With further research, MOR-1K could be exploited as a target for antagonists that reduce or prevent opioid-induced hyperalgesia.

背景
在接受阿片类药物治疗急性与慢性临床疼痛的人群中，部分人群会出现疼痛敏感性反常升高的现象，即阿片类诱导的痛觉过敏（opioid-induced hyperalgesia）。鉴于阿片类镇痛药物是当前临床可及的少数疼痛治疗方案之一，明确驱动阿片类诱导痛觉过敏的核心分子机制，对于降低其发生率至关重要。近期研究表明，μ阿片受体（mu opioid receptor）的剪接变体MOR-1K与阿片类诱导痛觉过敏的发生密切相关。人体遗传关联研究与细胞信号转导研究结果显示，MOR-1K可减弱阿片类镇痛应答，并通过Gs信号通路增强细胞活性。本研究首次直接验证了MOR-1K在阿片类诱导痛觉过敏中的作用。

方法与结果
为验证MOR-1K在阿片类诱导痛觉过敏中的作用，本研究首先在慢性吗啡给药前、给药期间及给药后，评估了小鼠对机械刺激与热刺激的疼痛应答。结果显示，三种遗传背景不同的小鼠品系（C57BL/6J、129S6及CXB7/ByJ）对吗啡的应答模式存在差异，且其MOR-1K基因表达模式也随之发生相应改变。129S6小鼠呈现镇痛应答，且该应答与MOR-1K基因表达水平的检测性下降相关；而CXB7/ByJ小鼠则表现出痛觉过敏应答，该应答与MOR-1K基因表达水平的检测性升高相关。此外，通过慢性鞘内注射siRNA敲低CXB7/ByJ小鼠的MOR-1K表达，不仅可阻止阿片类诱导痛觉过敏的发生，还能恢复吗啡的镇痛作用。

结论
上述研究结果表明，MOR-1K可能是阿片类诱导痛觉过敏发生的必要促成因素。通过进一步研究，MOR-1K可被开发为拮抗剂靶点，用于减轻或预防阿片类诱导痛觉过敏。