米贝地尔强化加巴喷丁对糖尿病大鼠神经病理性疼痛的镇痛效应

Mibefradil Potentiates Gabapentin's Efficacy of Rats with Diabetic Neuropathy Pain

目的观察米贝地尔强化加巴喷丁对糖尿病大鼠神经病理性疼痛的镇痛效应。方法选取健康雄性SD大鼠30只,6~7周龄,体重200~220g,通过腹腔注射链脲佐菌(60mg·kg-1)建立糖尿病神经病理性疼痛模型。将造模成功大鼠随机分为A组(生理盐水组)、B组(加巴喷丁30mg·kg-1组),C组(加巴喷丁60mg·kg-1组)及D组(加巴喷丁30mg·kg-1+米贝地尔10mg·kg-1组),各6只。A组予以生理盐水10mL·kg-1腹腔内注射;B组予以3mg·mL-1的加巴喷丁溶液10mL·kg-1腹腔注射;C组予以6mg·mL-1的加巴喷丁溶液10mL·kg-1腹腔注射;D组予以3mg·mL-1的加巴喷丁溶液+1mg·mL-1的米贝地尔溶液10mL·kg-1腹腔注射。各组大鼠每天每只给药1次。测定比较给药前(T0)、30min(T1)、60min(T2)、120 min(T3)、240min(T4)、480min(T5)时机械缩足阈值(PWT)和热缩足潜伏期(PWL)。结果与T0比较,C组和D组T1~T5时机械缩足阈值升高(P<0.05)。与A组比较,C和D组机械缩足阈值升高;与B组比较,C和D组机械缩足阈值升高(P<0.05);与C组比较,D组T4时机械缩足阈值升高(P<0.05)。与T0比较,B和C组T1~T3时热缩足潜伏期均延长(P<0.05)。D组T1~T4时热缩足潜伏期延长(P<0.05)。与A组比较,B和C组T1~T3时热缩足潜伏期延长;D组T1~T4时热缩足潜伏期延长(P<0.05)。与B组比较,D组T4时热缩足潜伏期延长,与C组比较,D组T4时热缩足潜伏期延长(P<0.05)。结论米贝地尔能够增强加巴喷丁对1型糖尿病大鼠神经病理性疼痛的镇痛效果,减少加巴喷丁用量,延长加巴喷丁有效作用时间。

Objective To investigate the antinociceptive effect of mibefradil potentiates gabapentin＇s efficacy of rats with diabetic neuropathy pain. Methods Thirty healthy male SD rats,aged 6-7 weeks and weighing200-220 g,were selected. The diabetic neuropathic pain model was established by intraperitoneal injection of streptozotocin（60 mg·kg^-1）. The diabetes mellitus rats were randomly divided into group A（normal saline group）,group B（gabapentin 30 mg·kg^-1 group）,group C（gabapentin 60 mg·kg^-1 group）and group D（gabapentin30 mg·kg^-1＋ mibapendil 10 mg·kg^-1 group）,with 6 rats in each group. Group A,physiological saline group,was given physiological saline 10 mL·kg^-1 by intraperitoneal injection;group B,30 mg·kg^-1 gabapentin group,was given 3 mg·m L^-1 gabapentin solution 10 mL·kg^-1 by intraperitoneal injection,qd; group C,60 mg·kg^-1 gabapentin group,was given 6 mg·m L^-1 gabapentin solution 10 mL·kg^-1 by intraperitoneal injection;group D,30 mg·kg^-1 gabapentin and 10 mg·kg^-1 mibefradil group,were given 3 mg·m L^-1 gabapentin solution and 1 mg·m L^-1 mibefradil solution,10 mL·kg^-1 by intraperitoneal injection. The paw withdrawal threshold（PWT）and paw withdrawal latency（PWL）were measured before at（T0）and 30 min（T1）,60 min（T2）,120 min（T3）,240 min（T4）,480 min（T5） after administration respectively. Results Compared with T0,the mechanical shrinkage threshold of group C and group D increased from T1 to T5（P〈0.05）. Compared with group A,the mechanical shrinkage thresholds of group C and D increased,and those of group B increased（P〈0.05）;and those of group C and D increased at T4（P〈0.05）. Compared with T0,the latency of heat shrinkable foot in B and C groups was prolonged at T1-T3（P〈0.05）. In group D,the latent period of heat shrinkable foot was prolonged at T1-T4（P〈0.05）. Compared with group A,the latency of febrile foot prolonged at T1-T3 in group B and C,and at T1-T4 in group D（P〈0.05）. Compared with group B,the latency of febrile foot contraction was prolonged at T4 in group D and at T4 in group C（P〈0.05）. Conclusion Combination therapy of mibefradil and gabapentin can increase gabapentin＇s antinociceptive effect in treating type-1 diabetic rats with painful diabetic neuropathy,decrease gabapentin＇s necessary dosage and prolong gabapentin＇s effective antinociceptive duration.