μ-Opioid receptor inhibition of substance P release from primary afferents disappears in neuropathic pain but not inflammatory pain.
μ-Opioid receptor inhibition of substance P release from primary afferents disappears in neuropathic pain but not inflammatory pain.
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DOI：
10.1016/j.neuroscience.2014.02.023
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发表时间：
2014-05-16
期刊：
影响因子：
3.3
通讯作者：
Marvizon, J. C. G.
中科院分区：
文献类型：
--
作者：
Chen, W.;McRoberts, J. A.;Marvizon, J. C. G.
神经性疼痛期间脊髓中的阿片镇痛作用受损。我们假设这是由于μ-阿片受体对初级传入神经递质释放的抑制作用减少所致。为了研究这种可能性，我们测量了坐骨神经慢性压迫性损伤 (CCI) 大鼠中神经激肽 1 受体 (NK1R) 内化时脊髓背角中 P 物质的释放。 CCI 对爪子的伤害性刺激会产生不一致的 NK1R 内化，这表明 CCI 后受伤神经传递伤害性信号的能力不同程度受损。这一观点得到了以下事实的支持：CCI 仅对外源性 P 物质诱导 NK1R 内化的能力或神经损伤部位中枢诱发的 P 物质的释放产生微小的变化。在随后的实验中，通过刺激 CCI 同侧的背根，在脊髓切片中诱导 NK1R 内化。我们观察到 CCI 大鼠中 μ-阿片受体激动剂 [D-Ala2、NMe-Phe4、Gly-ol5]-脑啡肽 (DAMGO) 对 P 物质释放的抑制完全丧失，但在假手术大鼠中则没有。相比之下，在弗氏完全佐剂和幼稚大鼠的后爪炎症后，DAMGO 仍然抑制 P 物质的释放。这种抑制作用的丧失并不是由于初级传入神经中 μ-阿片受体下调，因为它们与 P 物质的共定位在背根神经节神经元和背角初级传入纤维中都没有改变。总之，神经损伤消除了 μ-阿片受体对 P 物质释放的抑制，可能是通过阻碍其信号传导机制来实现的。
Opiate analgesia in the spinal cord is impaired during neuropathic pain. We hypothesized that this is caused by a decrease in μ-opioid receptor inhibition of neurotransmitter release from primary afferents. To investigate this possibility, we measured substance P release in the spinal dorsal horn as neurokinin 1 receptor (NK1R) internalization in rats with chronic constriction injury (CCI) of the sciatic nerve. Noxious stimulation of the paw with CCI produced inconsistent NK1R internalization, suggesting that transmission of nociceptive signals by the injured nerve was variably impaired after CCI. This idea was supported by the fact that CCI produced only small changes in the ability of exogenous substance P to induce NK1R internalization or in the release of substance P evoked centrally from site of nerve injury. In subsequent experiments, NK1R internalization was induced in spinal cord slices by stimulating the dorsal root ipsilateral to CCI. We observed a complete loss of the inhibition of substance P release by the μ-opioid receptor agonist [D-Ala2, NMe-Phe4, Gly-ol5]-enkephalin (DAMGO) in CCI rats but not in sham-operated rats. In contrast, DAMGO still inhibited substance P release after inflammation of the hind paw with complete Freund’s adjuvant and in naïve rats. This loss of inhibition was not due to μ-opioid receptor downregulation in primary afferents, because their colocalization with substance P was unchanged, both in dorsal root ganglion neurons and primary afferent fibers in the dorsal horn. In conclusion, nerve injury eliminates the inhibition of substance P release by μ-opioid receptors, probably by hindering their signaling mechanisms.
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