阿片受体三重激动剂KUST201的大鼠镇痛、耐受与戒断反应研究  

Evaluation of antinociception,tolerance and withdrawal abstinence of opioid receptor triple agonist KUST201 in rats

作　　者：李玖玲[1] 孔庆宏[1] 郁洁[1] 伊首璞[1] 李亚民[1] 王冠林[1] 沈悦海[1,2] 张宽仁[1] 

机构地区：[1]昆明理工大学生命科学与技术学院,云南昆明650500 [2]中国科学院昆明植物研究所植物化学与西部植物资源持续利用国家重点实验室,云南昆明650201

出　　处：《中国药理学通报》2016年第5期652-658,共7页Chinese Pharmacological Bulletin

基　　金：中国科学院昆明植物研究所植物化学与西部植物资源持续利用国家重点实验室开放课题(No P2015-KF04);云南省应用基础研究计划重点项目(No 2014FA002)

摘　　要：目的通过大鼠模型研究δ/μ/κ阿片受体三重激动剂KUST201(DPI-125)的镇痛、耐受和戒断反应。方法选用♂SD大鼠,肌肉注射给药,通过夹尾镇痛和热板镇痛模型实验测定KUST201的镇痛时效、ED_(50)和δ拮抗剂纳曲吲哚联用的影响。大鼠慢性耐受实验在每天给药后测量,同时考查纳曲吲哚联用的影响。戒断反应实验每天给药2次,连续4 d递增给药,d 4给药3 h后,用纳洛酮催促戒断,观察戒断反应。结果 KUST201的夹尾镇痛ED_(50)为0.34 mg·kg^(-1),热板镇痛ED_(50)为0.68 mg·kg^(-1),镇痛作用可维持1 h,2 h后作用消失。慢性耐受实验中,从d 3开始产生镇痛耐受,d 7作用消失。δ拮抗剂NTI可降低KUST201的镇痛作用。戒断反应实验中,剂量关系曲线在2~8倍夹尾镇痛ED_(50)范围内上升明显。结论与已报道的δ/μ/κ三重激动剂DPI-3290相比,KUST201的镇痛活性相似,慢性耐受反应较不明显,而戒断反应稍强。δ受体激动能协同增强μ受体激动的镇痛效果。Aim To investigate the antinociception, tolerance and withdrawal abstinence of δ/μ/κ opioid receptor triple agonist KUST201 ( DPI-125 ) in rats. Methods Male Sprague-Dawley rats were used to de-termine the time course of analgesic effects and ED50 effects of co-administration of naltrindole were assessed as well. In withdrawal experiments, KUST201 was ad-ministrated twice daily for 3 d with increasing doses each day. On the 4th day, the rats were given a single dose, challenged with naloxone 3 h later, and signs of abstinence were monitored. Results The ED50 values of KUST201 were 0. 34 mg·kg-1 in tail-pinch test and 0. 68 mg · kg-1 in hot-plate test. The antinociception actions of KUST201 started to decrease 1 h after ad-ministration, and disappeared after 2 h. In chronic tol-erance experiments, the antinociception actions started to decrease on d 3 , and completely disappeared on d 7 . Naltrindole could reduce the antinociceptive action of KUST201. In withdrawal experiments, abstinence scores increased significantly in the dose range between 2~8 times of tail-pinch ED50 . Conclusion Compared with previously reported δ/μ/κ triple agonist DPI-3290 , KUST201 exhibits similar antinociceptive effects in rats. The chronic tolerance to KUST201 actions de-velops less quickly, but the abstinence scores of KUST201 are slightly higher. The activation of δ-opi-oid receptor can synergistically enhance the antinoci-ception mediated by μ-receptor.

关 键 词：KUST201 DPI-125 镇痛 耐受 戒断 阿片受体三重激动剂 

分 类 号：R-332[医药卫生] R392.11