Raffa R B, Connelly C D, Martinez R P
Drug Discovery Research, R.W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477-0776.
Eur J Pharmacol. 1992 Jul 7;217(2-3):221-3. doi: 10.1016/0014-2999(92)90879-9.
Previous work demonstrated that a single subcutaneous injection of LiCl (10 mmol/kg; 18 h prior) significantly reduces the antinociceptive action of centrally administered (intracerebroventricular; i.c.v.) morphine in the tail-flick and that inositol-1,4,5-trisphosphate (IP3; 20 micrograms) restores the morphine response in LiCl-pretreated mice, implicating a phosphoinositide second messenger pathway in the mediation of morphine-induced analgesia. We now report that LiCl pretreatment shifted the antinociceptive dose-response curve produced by the opioid agonists morphine, [D-Ala2, MePhe4, Gly5-ol]enkephalin (DAMGO) and sufentanil in inverse order of their intrinsic efficacy. These results implicate the phosphoinositide pathway(s) as important determinant(s) of opioid efficacy and are interpreted as evidence for the existence of a second-messenger reserve for opioids of high efficacy and the possible role of the phosphoinositide pathway in the development of morphine tolerance.
先前的研究表明，单次皮下注射氯化锂（10 mmol/kg；提前18小时）可显著降低脑室内注射吗啡在甩尾实验中的镇痛作用，而肌醇-1,4,5-三磷酸（IP3；20微克）可恢复氯化锂预处理小鼠的吗啡反应，提示磷酸肌醇第二信使途径参与介导吗啡诱导的镇痛作用。我们现在报告，氯化锂预处理使阿片类激动剂吗啡、[D-丙氨酸2，甲硫苯丙氨酸4，甘氨酸5-醇]脑啡肽（DAMGO）和舒芬太尼产生的镇痛剂量-反应曲线按其内在效能的相反顺序发生偏移。这些结果表明磷酸肌醇途径是阿片类药物效能的重要决定因素，并被解释为高效能阿片类药物存在第二信使储备的证据以及磷酸肌醇途径在吗啡耐受性发展中可能发挥作用的证据。
