μ-Opioid receptors in primary sensory neurons are essential for opioid analgesic effect on acute and inflammatory pain and opioid-induced hyperalgesia
μ-Opioid receptors in primary sensory neurons are essential for opioid analgesic effect on acute and inflammatory pain and opioid-induced hyperalgesia
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DOI：
10.1113/jp277428
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发表时间：
2019-03-15
影响因子：
5.5
通讯作者：
Pan, Hui-Lin
中科院分区：
文献类型：
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作者：
Sun, Jie;Chen, Shao-Rui;Pan, Hui-Lin
疼痛和镇痛系统是复杂的，并且全身给予阿片类药物的作用可以通过在多个相互作用位点同时激活μ阿片受体（MORs，由Oprm 1基因编码）来介导。负责全身阿片类药物诱导的镇痛和痛觉过敏的MORs和电路的位点仍不清楚。先前的研究使用小鼠，其中MORs被从Nav1.8-或TRPV 1-表达神经元中去除，仅提供了关于外周MORs在体内阿片样物质作用中的作用的不完整和错误的观点。在本研究中，我们确定了在初级感觉神经元中表达的MORs在全身性阿片类药物给药产生的镇痛和痛觉过敏效应中的特定作用。我们产生了Oprm 1条件性基因敲除（Oprm 1-cKO）小鼠，其中莫尔表达从背根神经节神经元中完全缺失，并在脊髓中大幅减少，这通过免疫印迹和免疫细胞化学标记证实。阿片类药物诱导的抑制和增强的初级感觉输入被废除在Oprm 1-cKO小鼠。值得注意的是，全身给予吗啡有效地抑制了对照小鼠的急性热和机械伤害感受和持续性炎性疼痛，但对Oprm 1-cKO小鼠几乎没有影响。鞘内注射吗啡的镇痛作用也大大降低Oprm 1-cKO小鼠。此外，慢性吗啡治疗诱导的痛觉过敏在Oprm 1-cKO小鼠中不存在。我们的研究结果直接挑战的概念，临床相关的阿片类镇痛主要是由中央表达的MORs介导的。初级感觉神经元中的MORs，特别是那些在脊髓中的第一感觉突触突触前表达的MORs，对于阿片类镇痛和阿片类诱导的痛觉过敏都是至关重要的。
The pain and analgesic systems are complex, and the actions of systemically administered opioids may be mediated by simultaneous activation of mu-opioid receptors (MORs, encoded by the Oprm1 gene) at multiple, interacting sites. The loci of MORs and circuits responsible for systemic opioid-induced analgesia and hyperalgesia remain unclear. Previous studies using mice in which MORs are removed from Nav1.8- or TRPV1-expressing neurons provided only an incomplete and erroneous view about the role of peripheral MORs in opioid actions in vivo. In the present study, we determined the specific role of MORs expressed in primary sensory neurons in the analgesic and hyperalgesic effects produced by systemic opioid administration. We generated Oprm1 conditional knockout (Oprm1-cKO) mice in which MOR expression is completely deleted from dorsal root ganglion neurons and substantially reduced in the spinal cord, which was confirmed by immunoblotting and immunocytochemical labelling. Both opioid-induced inhibition and potentiation of primary sensory input were abrogated in Oprm1-cKO mice. Remarkably, systemically administered morphine potently inhibited acute thermal and mechanical nociception and persistent inflammatory pain in control mice but had little effect in Oprm1-cKO mice. The analgesic effect of intrathecally administered morphine was also profoundly reduced in Oprm1-cKO mice. Additionally, chronic morphine treatment-induced hyperalgesia was absent in Oprm1-cKO mice. Our findings directly challenge the notion that clinically relevant opioid analgesia is mediated mostly by centrally expressed MORs. MORs in primary sensory neurons, particularly those expressed presynaptically at the first sensory synapse in the spinal cord, are crucial for both opioid analgesia and opioid-induced hyperalgesia.