Shi Tiansheng, Hao Jing-Xia, Wiesenfeld-Hallin Zsuzsanna, Xu Xiao-Jun
Department of Physiology and Pharmacology, Section of Integrative Pain Research, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Department of Physiology and Pharmacology, Section of Integrative Pain Research, Karolinska Institutet, Stockholm, Sweden.
Scand J Pain. 2018 Oct 25;18(4):687-693. doi: 10.1515/sjpain-2018-0083.
Background and aims The clinical management of neuropathic pain remains a challenge. We examined the interaction between gabapentin and NMDA receptor antagonists dextromethrophan and MK-801 in alleviating neuropathic pain-like behaviors in rats after spinal cord or sciatic nerve injury. Methods Female and male rats were produced with Ischemic spinal cord injury and sciatic nerve injury. Gabapentin, dextromethorphan, MK-801 or drug combinations were injected with increasing doses. Mechanical response thresholds were tested with von Frey hairs to graded mechanical touch/pressure, and ethyl chloride spray was applied to assess the cold sensitivity before and after injuries. Results In spinally injured rats, gabapentin and dextromethorphan did not affect allodynia-like behaviors at doses of 30 and 20 mg/kg, respectively. In contrast, combination of 15 or 30 mg/kg gabapentin with dextromethorphan at 10 mg/kg produced total alleviation of allodynia to mechanical or cold stimulation. Further reducing the dose of gapapentin to 7.5 mg/kg and dextromethorphan to 5 mg/kg still produced significant effect. MK-801, another NMDA receptor antagonist, also enhanced the effect of gabapentin in spinally injured rats. Similar synergistic anti-allodynic effect between dextromethorphan and gabapentin was also observed in a rat model of partial sciatic nerve injury. No increased side effect was seen following the combination between gabapentin and dextromethorphan. Conclusions In conclusion, the present study suggested that combining NMDA receptor antagonists with gabapentin could provide synergistic effect to alleviate neuropathic pain and reduced side effects. Implications Combining NMDA receptor antagonists with gabapentin may provide a new approach in alleviating neuropathic pain with increased efficacy and reduced side effects.
背景与目的 神经性疼痛的临床管理仍然是一项挑战。我们研究了加巴喷丁与N-甲基-D-天冬氨酸（NMDA）受体拮抗剂右美沙芬和MK-801在减轻脊髓或坐骨神经损伤大鼠的神经性疼痛样行为方面的相互作用。方法 制作雌性和雄性大鼠的缺血性脊髓损伤和坐骨神经损伤模型。以递增剂量注射加巴喷丁、右美沙芬、MK-801或药物组合。用von Frey毛发测试分级机械触摸/压力的机械反应阈值，并应用氯乙烷喷雾评估损伤前后的冷敏感性。结果 在脊髓损伤的大鼠中，加巴喷丁和右美沙芬分别在30和20 mg/kg剂量时不影响痛觉过敏样行为。相比之下，15或30 mg/kg加巴喷丁与10 mg/kg右美沙芬联合使用可完全减轻对机械或冷刺激的痛觉过敏。将加巴喷丁剂量进一步降至7.5 mg/kg，右美沙芬剂量降至5 mg/kg仍产生显著效果。另一种NMDA受体拮抗剂MK-801也增强了加巴喷丁对脊髓损伤大鼠的作用。在部分坐骨神经损伤的大鼠模型中也观察到右美沙芬和加巴喷丁之间类似的协同抗痛觉过敏作用。加巴喷丁和右美沙芬联合使用后未观察到副作用增加。结论 总之，本研究表明，将NMDA受体拮抗剂与加巴喷丁联合使用可产生协同作用，减轻神经性疼痛并减少副作用。意义 将NMDA受体拮抗剂与加巴喷丁联合使用可能为减轻神经性疼痛提供一种新方法，提高疗效并减少副作用。
