脊髓水平NMDAR-ERK5信号通路在吗啡依赖大鼠戒断行为中的作用

目的 探讨脊髓水平N-甲基-D-天冬氨酸受体（N-methyl-D-aspartic acid receptor,NMDAR）-细胞外信号调节蛋白激酶5（extracellular signal-regulated kinase 5,ERK5）信号通路在吗啡依赖大鼠戒断行为中的作用.方法 成年雄性SD大鼠96只,体质量200～ 250 g,采用随机数字法,将实验动物随机分为四组（n=24）：对照组（A组）、戒断组（B组）、二甲基亚砜（DMSO）组（C组）、MK801组（D组）.采用剂量递增法皮下注射吗啡以建立大鼠吗啡依赖模型,第6天上午经腹腔注射纳洛酮,催促戒断症状出现,即建立吗啡戒断模型.采用行为药理学方法结合western blot技术,鞘内注射NMDAR抑制剂MK801,观察其对吗啡依赖大鼠戒断行为、戒断所致痛觉过敏及脊髓p-ERK5表达的影响.结果 A组大鼠腹腔注射纳洛酮后并未出现戒断症状及痛觉过敏.与A组相比,B组大鼠戒断症状评分（45.2±7.3）分]、痛觉过敏评分（14.4±3.7）分],C组大鼠戒断症状评分（44.7±6.2）分]、痛觉过敏评分（13.2±2.7）分],D组大鼠戒断症状评分（28.3±1.6）分]、痛觉过敏评分（5.9±11）分]明显增加（P＜0.05）;与C组相比,D组大鼠鞘内注射MK801后戒断症状评分（28.3±1.6）分]、痛觉过敏评分（5.9±1.1）分]明显降低（P＜0.05）.与A组相比,B组大鼠脊髓水平p-ERK5（12 848±621）、C组大鼠脊髓水平p-ERK5（12 579±396）表达显著上调（P＜0.05）;与C组大鼠脊髓水平p-ERK5（12 579±396）相比,D组大鼠鞘内注射MK801后脊髓水平p-ERK5（5123±546）表达显著下调（P＜0.05）.结论 脊髓水平NMDAR-ERK5信号通路参与吗啡依赖大鼠戒断症状的表达.

Roles of spinal N-methyl-D-aspartic acid receptor-extracellular signal-regulated protein kinase 5 signaling pathway in naloxone-induced withdrawal response in morphine-dependent rats

Objective To investigate the roles of spinal N-methyl-D-aspartic acid receptor-extracellular signal-regulated protein kinases 5 signaling pathway in naloxone-induced withdrawal response in morphine-dependent rats.Methods Ninety-six adult male SD rats weighting 230-250 g were randomly divided into 4 groups：control group,withdrawal group,DMSO group and MK801 group.Rats were subcutaneously injected with morphine.On day 6,rats were injected with naloxone （intraperitoneal） to precipitate morphine withdrawal syndromes.To identify the function of NMDAR-ERK5 signaling pathway in morphine withdrawal,morphine withdrawal-like behavior test and western blot technique were used in this research.The scores of morphine withdrawal symptom,morphine withdrawal-induced allodynia and the activation of ERK5 in spinal cord were observed after intrathecal injection of MK801.Results There was no withdrawal symptoms and withdrawal-induced allodynia in group A after intraperitoneal injection of naloxone.Compared with group A,withdrawal score （45.2±7.3）,score of withdrawal-induced allodynia （14.4±3.7） of group B,withdrawal score （44.7±6.2）,score of withdrawal-induced allodynia （13.2±2.7） of group C and withdrawal score （28.3±1.6）,score of withdrawal-induced allodynia （5.9± 1.1） of group D were significantly increased （P〈 0.05）.Compared with group C,the total withdrawal score （28.3 ± 1.6）,score of withdrawal-induced allodynia （5.9± 1.1） of group D were significantly decreased （P〈0.05）.Compared with group A,the expression of spinal p-ERK5 of group B （12848±621） and group C （12579±396） were significantly increased （P〈0.05）.Compared with group C,the expression of spinal p-ERK5 of group D （5 123±546） was significantly decreased （P〈0.05）.Condusion The signaling pathway of spinal N-methyl-D-aspartic acid receptor-extracellular signal-regulated protein kinases 5 contributes to naloxone-induced withdrawal response in morphine-dependent rats.