拮抗脊髓细胞外信号调节蛋白激酶5对吗啡依赖大鼠戒断行为的影响

目的探讨脊髓水平细胞外信号调节蛋白激酶5（extra—cellular signal-regulated protein kinase5，ERK5）在大鼠吗啡戒断行为中的作用。方法成年雄性SD大鼠96只，体质量200～250g，采用随机数字法，将其分为4组（每组n=24）：生理盐水一纳洛酮-DMSO组（A组）、生理盐水一纳洛酮一BIX02188组（B组）、吗啡一纳洛酮一DMSO组（C组）、吗啡一纳洛酮一BIX02188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。结合药理学手段鞘内注射ERK5特异性抑制剂BIX02188，观察其对吗啡依赖大鼠戒断行为及戒断所致的痛觉过敏的影响。结果A、B两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，C组大鼠戒断后咬牙（7．5±1．1）分、湿狗样抖动（4．6＋0．7）分、戒断后跳跃（5．3＋0．7）分、扭体（8．9±I．9）分、腹泻（7．1±1．6）分、流涎（2．8＋0．6）分、体质量减轻（7．9＋0．9）分、戒断症状总评分（44．8＋5．9）分、痛觉过敏评分（14．6±2．4）分及D组大鼠戒断后咬牙（3．1±0．5）分、湿狗样抖动（1．5＋0．D）分、戒断后跳跃（2．2＋0．5）分、扭体（7．9±1．6）分、腹泻（1．8＋0．5）分、流涎（2．8＋0．9）分、体质量减轻（3．7±0．6）分、戒断症状总评分（23．1±1．3）分、痛觉过敏评分（3．5±1．1）分明显增加（P〈O．05）；与C组相比，D组大鼠鞘内注射BIX02188后戒断症状如咬牙（3．1±0．5）分、湿狗样抖动（1．50．4）分、戒断后跳跃（2．2±0．5）分、腹泻（1．8＋0．5）分、体质量减轻（3．70．6）分、戒断症状总评分（23．1±I．3）分、痛觉过敏评分（3．5±1．1）分明显得到缓解（P〈0．05）；而扭体（7．9±1．6）分及流涎（2．80．9）分并未得到缓解，差异无统计学意义（尸〉0．05）。结论通过鞘内注射BIX02188拮抗脊髓ERK5可显著减轻吗啡依赖大鼠的戒断症状。

Effect of inhibition of spinal extracellular signal-regulated protein kinase 5 on morphine withdrawal in rats with morphine dependence

Objective To investigate the roles of spinal extracellular signal-regulated protein kinases 5 （ERK5） on morphine withdrawal in rats. Methods Ninety-six male and adult SD rats weighting 230-250 g were randomly divided into saline-naloxone-DMSO group （group A） , saline-naloxone-BIX02188 group （group B） , mor- phine-naloxone-DMSO group （group C） and morphine-naloxone-BIX02188 group （group D）. To set up morphine dependent model ,rats were subcutaneously injected with morphine in the increasing dosage method. On day 6,4 h after the injection of morphine, rats were injected with naloxone （intraperitoneal） to precipitate morphine withdraw- al syndrome. The scores of morphine withdrawal symptom and morphine withdrawal-induced allodynia were ob- served after intratheeal injection of ERK5 inhibitor BIX02188. Result There were not withdrawal symptoms and withdrawal-induced allodynia in group A and B after intraperitoneal injection of naloxone. Compared with group A, teeth chatting （ 7.5 ~ 1.1 ）, wet dog shacks （ 4.6 ± 0.7 ）, jump （ 5.3 ± 0.7 ）, abnormal position （ 8.9 ± 1.9 ）, diarrhea （ 7.1 ± 1.6 ） , salivation （ 2.8 ± 0.6 ）, weight loss （ 7.9 ± 0.9 ） , total withdrawal score （ 44.8 ± 5.9 ）, score of withdrawal- induced allodynia （14.6±2.4） of group C and teeth chatting （ 3.1 ±0.5）, wet dog shacks （ 1.5±0.4）, jump （ 2.2± 0.5 ）, abnormal position （ 7.9± 1.6）, diarrhea （ 1.8±0.5 ）, salivation （ 2.8±0.9）, weight loss （ 3.7±0.6）, total with- drawal score （ 23.1 ± 1.3） and score of withdrawal-induced allodynia （ 3.5 ± 1.1 ） of group D were significantly in- creased （P〈0.05）. Compared with, group C ,teeth chatting （3.1~0.5） ,wet dog shacks （1.5±0.4） ,jump （2.2~0.5） ,diarrhea （1.8-±0.5） ,weight loss （3.7~0.6） and total withdrawal score （23.1~1.3）,score of withdrawal-induced allodynia （3.5~ 1.1） of group D were significantly decreased （/o〈0.05）. But there was not significant change in abnormal position （7.9±1.6） and sali- vation （2.8~0.9）. Condusion Inhibition of the activation of spinal cord ERK5 can significantly alleviate withdrawal symp- toms of morphine dependent rats by intrathecal injection BIX02188.