阿片受体三重激动剂KUST201的大鼠镇痛、耐受与戒断反应研究

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、ED50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 ED50为0．34 mg · kg-1,热板镇痛ED50为0．68 mg·kg-1,镇痛作用可维持1 h,2h后作用消失。慢性耐受实验中,从d3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ED50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.