The difference between methadone and morphine in regulation of delta-opioid receptors underlies the antagonistic effect of methadone on morphine-mediated cellular actions

To investigate the cellular and molecular basis for using methadone in subs titution therapy for morphine addiction, the difference between methadone a nd morphine in causing desensitization of delta-opioid receptors was examin ed, and the effects of methadone pretreatment on opiate-induced inhibition of forskolin-stimulated cAMP accumulation was studied. Methadone substantia lly attenuated the ability of [D-Ala(2),D-Leu(5)]enkephalin (DADLE), morphi ne and methadone to inhibit forskolin-stimulated cAMP accumulation. Methado ne was able to block the morphine-induced compensatory increase in intracel lular cAMP levels and naloxone-precipitated cAMP overshoot after chronic ex posure to morphine. The protein kinase inhibitor (1-5-isoquinolinesulfony)- 2-methylpiperazine) (H-7) could significantly block the chronic methadone t reatment-induced loss of the ability of DADLE to inhibit adenylate cyclase. The protein kinase inhibitor chelerythrine was able to block the acute met hadone treatment-induced loss of the ability of DADLE to inhibit adenylate cyclase. In contrast, morphine did not cause a substantial desensitization of the delta-opioid receptor. These results indicate that methadone is diff erent from morphine in its regulation of the delta-opioid receptor. In addi tion, these results also indicate that the mechanisms of delta-opioid recep tor desensitization induced by acute and chronic methadone treatment are di fferent. (C) 1999 Elsevier Science B.V. All rights reserved.