加巴喷丁通过δGABA_A受体缓解神经病理性疼痛抑郁行为

Gabapentin Alleviates Neuropathic Pain and Depressive Behavior through δGABA_A Receptors

摘要: 目的：探讨加巴喷丁对神经病理性疼痛抑郁行为的影响和机制。方法：将36只SPF级雄性C57/B6小鼠8周龄采用随机数字表法均分为3组(n = 12)：假手术组(Sham组)、神经病理性疼痛组(CCI组)和加巴喷丁组(Gap组)。采用坐骨神经慢性缩窄法(Chronic Constriction Injury, CCI)建立神经病理性疼痛模型，术后第30天Gap组腹腔注射加巴喷丁100 mg/kg，Sham和CCI组给予等容量生理盐水，连续7天。术前和术后第7、14、21、28和40 d测定各组大鼠机械缩足反应阈值(PMWT)和热缩足潜伏期(PTWL)，评价小鼠疼痛行为；术前和术后第28、40天，采用悬尾实验(TST)和高架十字迷宫实验(EPM)，评价小鼠抑郁行为。通过蛋白质免疫印迹检测小鼠海马δGABA_A受体蛋白表达。结果：与Sham组相比，CCI组术后第7、14、21、28和40 d的PMWT显著下降、PTWL显著缩短(P < 0.05)；术后第28 d和40 d，悬尾实验(TST)的不动时间显著延长(P < 0.05)；高架十字迷宫测试(EPM)探索开放臂的时间显著减少(P < 0.05)；海马δGABA_A受体蛋白表达显著下降(P < 0.05)；Gap组术后第28 d PMWT显著下降、PTWL显著缩短(P < 0.05)；悬尾实验(TST)的不动时间显著延长(P < 0.05)；高架十字迷宫测试(EPM)探索开放臂的时间显著减少(P < 0.05)。与CCI组相比，Gap组术后第40 d PMWT显著增加，PTWL显著延长(P < 0.05)；悬尾实验(TST)的不动时间显著减少(P < 0.05)；高架十字迷宫测试(EPM)探索开放臂的时间显著增加(P < 0.05)；海马δGABA_A受体蛋白表达显著增加(P < 0.05)。结论：加巴喷丁缓解神经病理性疼痛行为的同时，可以改善神经病理性疼痛相关抑郁行为，可能与加巴喷丁增加海马δGABA_A受体的表达有关。

Abstract: Objective: Discuss the effects and mechanisms of gabapentin on neuropathic pain and depressive behavior. Methods: 36 SPF grade male C57/B6 mice, 8 weeks old, were randomly divided into 3 groups (n = 12) using a random number table: sham group (Sham group), neuropathic pain group (CCI group), and gabapentin group (Gap group). The neuropathic pain model was established using the chronic constriction injury (CCI) of the sciatic nerve. On the 30th day post-operation, the Gap group was injected intraperitoneally with gabapentin at 100 mg/kg, while the Sham and CCI groups were given an equal volume of normal saline for 7 consecutive days. Before surgery and on day post operative 7, 14, 21, 28, and 40, the mechanical withdrawal threshold (PMWT) and thermal withdrawal latency (PTWL) were measured in each group of rats to evaluate pain behavior; before surgery and on day post operative 28 and 40, the tail suspension test (TST) and elevated plus maze (EPM) were used to assess depressive behavior in mice. Detection of δGABA_A receptor protein expression in mouse hippocampus by Western blotting. Results: Compared with the Sham group, the CCI group showed a significant decrease in PMWT and a significant shortening of PTWL on postoperative days 7, 14, 21, 28, and 40 (P < 0.05); on postoperative days 28 and 40, the immobility time in the tail suspension test (TST) was significantly prolonged (P < 0.05); the time spent exploring the open arms in the elevated plus maze test (EPM) was significantly reduced (P < 0.05); hippocampal δGABA_A receptor protein expression was significantly decreased (P < 0.05); the Gap group showed significantly decreased PMWT and significantly shortened PTWL on postoperative day 28 (P < 0.05); the immobility time in the tail suspension test (TST) was significantly prolonged (P < 0.05); the time spent exploring the open arms in the elevated plus maze test (EPM) was significantly reduced (P < 0.05). Compared with the CCI group, the Gap group exhibited significantly increased PMWT and significantly prolonged PTWL on postoperative day 40 (P < 0.05); the immobility time in the tail suspension test (TST) was significantly reduced (P < 0.05); the time spent exploring the open arms in the elevated plus maze test (EPM) was significantly increased (P < 0.05); hippocampal δGABA_A receptor protein expression was significantly increased (P < 0.05). Conclusion: Gabapentin can alleviate neuropathic pain behaviors while improving depression behaviors associated with neuropathic pain, which may be related to the increase in the expression of hippocampal δGABA_A receptors by gabapentin.