title: Chronic neurosteroid treatment prevents the development of morphine tolerance and attenuates abstinence behavior in mice.
abstract: The effect of neurosteroids on the development of morphine tolerance and dependence was examined in mice. Development of tolerance to the antinociceptive 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 testing. Concomitant chronic administration of neurosteroids, allopregnanolone (0.5 mg/kg), pregnenolone sulfate (2 and 5 mg/kg) or dehydroepiandrosterone sulfate (2 and 5 mg/kg), followed by morphine (10 mg/kg) prevented the development of tolerance to the antinociceptive effect of morphine and suppressed the naloxone-precipitated withdrawal jumps. In contrast, dehydroepiandrosterone acetate (5 mg/kg) failed to modulate the morphine tolerance and dependence. The inhibitory effect was also seen upon concomitant administration of a neurosteroid precursor, progesterone (1-10 mg/kg), and a mitochondrial diazepam binding inhibitor receptor agonist, 4'-chlordiazepam (0.25-1 mg/kg), while an adrenocorticosteroid, 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. Neurosteroids themselves, at doses employed in the study, did not exert any effects on antinociception. These results support a role for neurosteroids in the development of tolerance to and dependence on morphine and suggest the potential utility of specific neuroactive steroids in its treatment.
authors.affiliation: Department of Pharmacology, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
authors.forename: D S
authors.initials: DS
authors.lastname: Reddy
authors.forename: S K
authors.initials: SK
authors.lastname: Kulkarni
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D004361:Drug Tolerance; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D011280:Pregnanolone / Q000494:pharmacology; D011284:Pregnenolone / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D013256:Steroids / Q000494:pharmacology*; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control* / Q000523:psychology
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D013256:Steroids; D009270:Naloxone; D003687:Dehydroepiandrosterone; D011284:Pregnenolone; D009020:Morphine; D011280:Pregnanolone