CHRONIC NEUROSTEROID TREATMENT PREVENTS THE DEVELOPMENT OF MORPHINE-TOLERANCE AND ATTENUATES ABSTINENCE BEHAVIOR IN MICE

The effect of neurosteroids on the development of morphine tolerance a nd dependence was examined in mice. Development of tolerance to the an tinociceptive effect of morphine sulfate (10 mg/kg, twice daily for 9 days) was measured in the tail-flick test and dependence was assessed from naloxone (2 mg/kg)-precipitated withdrawal jumps on day 10 of tes ting. Concomitant chronic administration of neurosteroids, allopregnan olone (0.5 mg/kg), pregnenolone sulfate (2 and 5 mg/kg) or dehydroepia ndrosterone sulfate (2 and 5 mg/kg), followed by morphine (10 mg/kg) p revented the development of tolerance to the antinociceptive effect of morphine and suppressed the naloxone-precipitated withdrawal jumps. I n contrast, dehydroepiandrosterone acetate (5 mg/kg) failed to modulat e the morphine tolerance and dependence. The inhibitory effect was als o seen upon concomitant administration of a neurosteroid precursor, pr ogesterone (1-10 mg/kg), and a mitochondrial diazepam binding inhibito r receptor agonist, B-chlordiazepam (0.25-1 mg/kg), while an adrenocor ticosteroid, hydrocortisone (1 and 10 mg/kg), failed to do so. However , acute treatment with these neurosteroids was not associated with any decrease in withdrawal jumping behavior in morphine-dependent mice. N eurosteroids themselves, at doses employed in the study, did not exert any effects on antinociception. These results support a role for neur osteroids in the development of tolerance to and dependence on morphin e and suggest the potential utility of specific neuroactive steroids i n its treatment. (C) 1997 Elsevier Science B.V.