Potential mechanisms of neurosteroid-induced attenuation of morphine tolerance and dependence
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Objective: The modulatory role of -aminobutyric acid (GABA)- benzodiazepine-Cl- channel, neuronal Ca2+ channels, N-methyl-D-aspartate (NMDA) and mitochondrial diazepam binding inhibitor receptors in the neurosteroid-induced attenuation of morphine tolerance and dependence was investigated. Methods: Mice were rendered dependent on morphine (10 mg/kg, twice daily for 9 days) and the development of tolerance was assessed by tail-flick test. The abstinence behaviour was evaluated by naloxone (2 mg/kg)-induced jumping. Results: Concomitant treatment with neurosteroid pregnenolone sulfate (2 mg/kg), progesterone (5 mg/kg) or 4'-chlordiazepam (0.5 mg/kg) significantly prevented the development of tolerance and also inhibited the naloxone (2 mg/kg)-induced withdrawal jumping in morphine- dependent mice. The effect of 4'-chlordiazepam was blocked by the mitochondrial diazepam binding inhibitor receptor antagonist PK11195 (2 mg/kg), but not by flumazenil (2 mg/kg), a selective benzodiazepine receptor antagonist. In contrast, the effect of progesterone was not affected by PK11195 or flumazenil. As expected, the development of tolerance and dependence observed upon chronic morphine was inhibited by the Ca2+ channel blocker nifedipine or an NMDA receptor antagonist dizocilpine. Further, a combined chronic administration of nifedipine together with neurosteroids pregnenolone sulfate, progesterone or 4'-chlordiazepam led to an additive inhibitory effects on morphine tolerance or dependence, whereas the dizocilpine effect could not be increased by coadministration of the neurosteroids. Conclusion: The results indicate a role for dihydropyridine- sensitive Ca2+ channels in the action of neurosteroids and mitochondrial diazepam binding receptors in the 4'-chlordiazepm on the development of tolerance and dependence on morphine. Further, the direct involvement of GABA(A)/benzodiazepine receptor-mediated chloride channel control in the observed neurosteroid effects cannot be unequivocally ruled out.
