IS THE REDUCED EFFICACY OF MORPHINE IN DIABETIC RATS CAUSED BY ALTERATIONS OF OPIATE RECEPTORS OR OF MORPHINE PHARMACOKINETICS

Because it generally is admitted that neuropathic pain is resistant to opioid analgesia, we investigated the effect of morphine on hyperalge sia in streptozocin-induced diabetes in rats. The antinociceptive effe ct of morphine (0.5-4 mg/kg i.v.) on mechanical (paw pressure test), t hermal (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 recept or agonists and the pharmacokinetics of morphine and its glucuronide m etabolites morphine 3-glucuronide and morphine 6-glucuronide were dete rmined. K-D and B-max values for [H-3][D-Ala(2), (Me)Phe(4),Gly(ol)(5) ]enkephalin and [H-3][D-Pen(2),D-Pen(5)]enkephalin to cerebral mu and delta opiate receptors were not altered by diabetes. Likewise, the pla sma 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 m orphine were increased in diabetic rats, which suggests that the diabe tes-induced glycosylation of proteins might increase the distribution of morphine in the aqueous compartment. These data indicate that the r educed analgesic effect of morphine caused by diabetes cannot be expla ined by a decrease in opiate-receptor affinity or density but rather b y kinetic alteration of morphine (increase of total clearance and of v olume of distribution in comparison with healthy animals).