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 substitution therapy for morphine addiction, the difference between methadone and morphine in causing desensitization of delta-opioid receptors was examined, and the effects of methadone pretreatment on opiate-induced inhibition of forskolin-stimulated cAMP accumulation was studied. Methadone substantially attenuated the ability of [D-Ala2,D-Leu5]enkephalin (DADLE), morphine and methadone to inhibit forskolin-stimulated cAMP accumulation. Methadone was able to block the morphine-induced compensatory increase in intracellular cAMP levels and naloxone-precipitated cAMP overshoot after chronic exposure to morphine. The protein kinase inhibitor (1-5-isoquinolinesulfony)-2-methylpiperazine) (H7) could significantly block the chronic methadone treatment-induced loss of the ability of DADLE to inhibit adenylate cyclase. The protein kinase inhibitor chelerythrine was able to block the acute methadone 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 different from morphine in its regulation of the delta-opioid receptor. In addition, these results also indicate that the mechanisms of delta-opioid receptor desensitization induced by acute and chronic methadone treatment are different.
Department of Neuropharmacology, Beijing Institute of Pharmacology and Toxicology, China. jgliu@mailexcite.com
J G
JG
Liu
X P
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Liao
Z H
ZH
Gong
B Y
BY
Qin
D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism; D000470:Alkaloids; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D053119:Benzophenanthridines; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D016308:Enkephalin, Leucine-2-Alanine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006822:Hybrid Cells; D008691:Methadone / Q000494:pharmacology*; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D000701:Analgesics, Opioid; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D009292:Narcotic Antagonists; D010617:Phenanthridines; D017465:Receptors, Opioid, delta; D005576:Colforsin; D009270:Naloxone; D016308:Enkephalin, Leucine-2-Alanine; D009020:Morphine; D000242:Cyclic AMP; C016299:chelerythrine; D011493:Protein Kinase C; D000262:Adenylyl Cyclases; D008691:Methadone