右美托咪定通过抑制脊髓小胶质细胞活化减轻吗啡戒断反应痛觉过敏

目的 探讨右美托咪定（Dexmedetomidine, Dex）对吗啡（Morphine, M）戒断反应中痛觉过敏的影响及机制。方法 吗啡腹腔注射创建小鼠吗啡戒断反应痛觉过敏模型，根据药物处理随机分为Control、M、M/Dex、M/Min、M/Dex/Min。Von Frey测定各组小鼠机械性痛阈改变，免疫荧光检测脊髓背角小胶质细胞激活变化，Western blot和PCR检测各组脊髓降钙素基因相关肽（Calcitonin gene-related peptide, CGRP）蛋白和mRNA表达变化，并用微透析测定脊髓内炎症因子水平，最后电生理观察右美托咪定对脊髓抑制性突触后电流（Spontaneous inhibitory postsynaptic current, sIPSC）的影响。结果 同Control组相比，M组机械性痛阈显著降低，吗啡戒断痛觉过敏模型创建成功，同时小胶质细胞激活增加，脊髓背角CGRP及炎症因子表达增加。同M组相比，M/Dex、M/Min、M/Dex/Min组痛阈显著升高在模型创建后4h最明显，同时三组小胶质细胞激活均明显减少，脊髓背角CGRP及炎症因子表达降低。电生理结果显示右美托咪定显著增强脊髓背角神经元sIPSC的振幅和频率。结论 右美托咪定通过抑制脊髓小胶质细胞减少CGRP的表达并减轻脊髓炎症反应，且能够增强脊髓抑制性电活动，从而缓解吗啡戒断反应中的痛觉过敏。

Dexmedetomidine alleviates hyperalgesia in morphine withdrawal syndrome by inhibiting microglia activation in spinal cord

Objective To investigate the effect and mechanism of dexmedetomidine (Dex) on hyperalgesia in morphine (M) withdrawal mice. Methods Hyperalgesia model was established by multiple morphine administration, and mice were randomly divided into Control, M, M/Dex, M/Min, M/Dex/Min groups following drug treatment. Mechanical pain thresholds were tested by Von Frey, microglia activation in spinal dorsal horn were observed by immunofluorescence, calcitonin gene-related peptide (CGRP) expressions were detected by Western blot and PCR, and levels of inflammatory factors in spinal cord was determined by microdialysis. Finally, the effect of dexmedetomidine on spontaneous inhibitory postsynaptic current (sIPSC) was observed by electrophysiology. Results Compared with Control group, mechanical pain threshold in M was significantly decreased, suggesting the successfully establishment of hyperalgesia model of morphine withdrawal, followed by increased microglia activation, increased CGRP expression and inflammatory factors releases. Compared with M group, pain thresholds in M/Dex, M/Min, M/Dex/Min increased significantly, and microglia activation, CGRP expression and inflammatory factors release was significantly decreased. The electrophysiology results showed that the amplitude and frequency of sIPSC in dexmedetomidine perfusion was enhanced. Conclusion Dexmedetomidine reduces inflammatory responses mediated by CGRP through inhibiting microglia activation in spinal cord, and enhances the spinal inhibitory electrical activities to acquire the alleviation of hyperalgesia in morphine withdrawal mice.