INHIBITION OF MORPHINE-TOLERANCE AND DEPENDENCE BY DIAZEPAM AND ITS RELATION TO MU-OPIOID RECEPTORS IN THE RAT-BRAIN AND SPINAL-CORD

We have recently observed that concomitant administration of diazepam to morphine pellet implanted rats results in the inhibition of the dev elopment of morphine tolerance and dependence. We have now analyzed mu -opioid receptors in rats treated with morphine and diazepam for 5 day s by using [H-3]-DAMGO for binding studies. Male Sprague-Dawley rats w ere made tolerant and dependent by subcutaneous (s.c.) implantation of six morphine pellets (two pellets on the first day, and four on the s econd day). Diazepam (0.25 mg/kg b.wt) was injected once daily intrape ritoneally (i.p.) for 5 days. Control rats were implanted with placebo pellets and injected once daily with saline or diazepam (i.p.). Anima ls were administered s.c. naloxone (10 mg/kg) to induce naloxone-preci pitated withdrawal syndrome on the final day of the experiment (day 5) . There was an up-regulation of mu-receptor (B-max increased) in the s pinal cord of morphine tolerant (+139%) and dependent (+155%) rats com pared to saline treated animals. Diazepam treatment abolished the up-r egulation of mu-receptors in spinal cord of morphine treated rats. In the cortex, B-max was not affected in morphine tolerant or dependent r ats but it decreased by 38% in morphine tolerant and 65% in morphine d ependent rats treated with diazepam. The K-d of mu-receptors increased in the cortex, striatum and hypothalamus of morphine dependent rats. Diazepam treatment decreased the K-d of mu-receptors in the cortex of morphine tolerant and hypothalamus of morphine-dependent rats. These r esults suggest that diazepam treatment antagonizes the up-regulation o f CNS mu-receptors observed in morphine tolerant rats. In addition, mo rphine tolerance and dependence may be associated with conversion of m u-opioid receptors to mu-constitutive opioid receptors that are less active, and this conversion is prevented in the brain of animals treat ed with diazepam. (C) 1998 Elsevier Science B.V. All rights reserved.