INHIBITION OF MORPHINE-TOLERANCE AND DEPENDENCE BY DIAZEPAM AND ITS RELATION TO THE CNS MET-ENKEPHALIN LEVELS

The effect of diazepam on the development of morphine tolerance and de pendence was investigated. Male Sprague-Dawley rats were rendered tole rant and dependent by subcutaneous implantation of six morphine pellet s. Diazepam (0.025, 0.25 or 2.5 mg/kg body weight) was once daily inje cted intraperitoneally into rats starting on the first day of implanta tion. Antinociception was measured by tail-flick (TF) and hot plate (H P) tests, and the extent of sedation determined by a rotarod test befo re and one hour after diazepam injections everyday for 5 days. Physica l dependence on morphine was assessed by an antagonist-precipitated ab stinence syndrome on the fifth day of treatment by injecting naloxone 10 mg/kg subcutaneously. Diazepam (0.025-2.5 mg/kg body weight) did no t produce significant antinociception or sedation (sensorimotor impair ment) in rats implanted with placebo pellets. Diazepam (0.25 and 2.5 m g/kg) inhibited tolerance to TF antinociception in rats implanted with morphine pellets. Sedation as evidenced by sensorimotor impairment in duced by morphine pellet implantation was not influenced by diazepam ( 0.025-2.5 mg/kg). Diazepam administration (0.25 mg/kg) also decreased the degree of jumping behavior observed following naloxone injection i n morphine pellet implanted rats. Serum morphine concentration in morp hine-diazepam treated rats was not significantly different from that i n morphine-saline treated rats. Finally, a decrease in the Met-enkepha lin levels observed in the hypothalamus, hippocampus, cortex and spina l cord of morphine dependent rats was reversed by injecting diazepam a long with morphine pellet implantation. These results suggest that dia zepam inhibits morphine tolerance and dependence, and also prevents mo rphine-induced decrease in the CNS Met-enkephalin levels in morphine d ependent rats.