Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia.
Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia.
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MU阿片类剪接变体MOR-1K有助于阿片类药物诱导的痛觉过敏的发展。
DOI：
10.1371/journal.pone.0135711
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Nackley AG
中科院分区：
文献类型：
--
作者：
Oladosu FA;Conrad MS;O'Buckley SC;Rashid NU;Slade GD;Nackley AG
接受阿片类药物治疗急性和慢性临床疼痛的人群中的一个子集出现了疼痛敏感性的矛盾增加，称为阿片类药物诱导的痛觉过敏。鉴于阿片类镇痛药是少数几种可用于临床疼痛的治疗方法之一，确定驱动阿片类药物诱导的痛觉过敏的关键分子机制以降低其患病率至关重要。最近的证据表明，在阿片类药物诱导的痛觉过敏的出现中，μ阿片受体的剪接变体（称为莫尔-1 K）。来自人类遗传关联和细胞信号传导研究的结果表明，莫尔-1 K有助于降低阿片类镇痛反应，并通过Gs信号传导产生增加的细胞活性。在这里，我们进行了第一项研究，以直接测试莫尔-1 K在阿片类药物诱导的痛觉过敏中的作用。为了研究莫尔-1 K在阿片类药物诱导的痛觉过敏中的作用，我们首先在慢性吗啡给药之前、期间和之后评估了对机械和热刺激的疼痛反应。结果表明，遗传多样性小鼠品系（C57 BL/6 J，129 S6和CXB 7/ByJ）表现出不同的吗啡反应谱，莫尔-1 K基因表达模式也发生了相应的变化。129 S6小鼠表现出与测得的莫尔-1 K基因表达水平降低相关的镇痛反应，而CXB 7/ByJ小鼠表现出与测得的莫尔-1 K基因表达水平升高相关的痛觉过敏反应。此外，通过长期鞘内siRNA给药敲低CXB 7/ByJ小鼠中的莫尔-1 K不仅阻止了阿片类药物诱导的痛觉过敏的发展，而且揭示了吗啡镇痛。这些发现表明，莫尔-1 K可能是阿片类药物诱导的痛觉过敏的发展的必要贡献者。随着进一步的研究，莫尔-1 K可以被开发为减少或预防阿片类药物诱导的痛觉过敏的拮抗剂的靶标。
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. 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. 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.