Courteix C, Bourget P, Caussade F, Bardin M, Coudore F, Fialip J, Eschalier A
Equipe NPPUA, Laboratoire de Pharmacologie, Faculté de Pharmacie, F-63001 Clermont-Ferrand Cedex, France.
J Pharmacol Exp Ther. 1998 Apr;285(1):63-70.
Because it generally is admitted that neuropathic pain is resistant to opioid analgesia, we investigated the effect of morphine on hyperalgesia in streptozocin-induced diabetes in rats. The antinociceptive effect of morphine (0.5-4 mg/kg i.v.) on mechanical (paw pressure test), thermal (tail immersion test) and chemical (formalin test) hyperalgesia was reduced. To clarify the mechanisms involved in the alteration of morphine analgesia, the binding characteristics of mu and delta receptor agonists and the pharmacokinetics of morphine and its glucuronide metabolites morphine 3-glucuronide and morphine 6-glucuronide were determined. KD and Bmax values for [3H][D-Ala2,(Me)Phe4, Gly(ol)5]enkephalin and [3H][D-Pen2,D-Pen5]enkephalin to cerebral mu and delta opiate receptors were not altered by diabetes. Likewise, the plasma maximal concentration of morphine and metabolites, as well as the area under the curve, did not differ between diabetic and normal rats. Only the total clearance and the apparent volume of distribution of morphine were increased in diabetic rats, which suggests that the diabetes-induced glycosylation of proteins might increase the distribution of morphine in the aqueous compartment. These data indicate that the reduced analgesic effect of morphine caused by diabetes cannot be explained by a decrease in opiate-receptor affinity or density but rather by kinetic alteration of morphine (increase of total clearance and of volume of distribution in comparison with healthy animals).
由于人们普遍认为神经性疼痛对阿片类镇痛药物具有抗性，我们研究了吗啡对链脲佐菌素诱导的糖尿病大鼠痛觉过敏的影响。吗啡（0.5 - 4mg/kg静脉注射）对机械性（爪部压力试验）、热性（尾部浸没法试验）和化学性（福尔马林试验）痛觉过敏的镇痛作用减弱。为阐明吗啡镇痛作用改变所涉及的机制，测定了μ和δ受体激动剂的结合特性以及吗啡及其葡萄糖醛酸代谢产物吗啡3 - 葡萄糖醛酸和吗啡6 - 葡萄糖醛酸的药代动力学。糖尿病并未改变[3H][D - Ala2,(Me)Phe4,Gly(ol)5]脑啡肽和[3H][D - Pen2,D - Pen5]脑啡肽与脑μ和δ阿片受体的KD值和Bmax值。同样，糖尿病大鼠和正常大鼠之间吗啡及其代谢产物的血浆最大浓度以及曲线下面积并无差异。糖尿病大鼠仅吗啡的总清除率和表观分布容积增加，这表明糖尿病诱导的蛋白质糖基化可能增加了吗啡在水相中的分布。这些数据表明，糖尿病导致吗啡镇痛作用减弱不能用阿片受体亲和力或密度降低来解释，而应由吗啡的动力学改变（与健康动物相比总清除率和分布容积增加）来解释。
