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

Eur J Pharmacol. 1999 Jun 4;373(2-3):233-9. doi: 10.1016/s0014-2999(99)00270-8.


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.

Publication types

  • Comparative Study

MeSH terms

  • Adenylyl Cyclases / drug effects
  • Adenylyl Cyclases / metabolism
  • Alkaloids
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Benzophenanthridines
  • Colforsin / pharmacology
  • Cyclic AMP / metabolism
  • Enkephalin, Leucine-2-Alanine / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Hybrid Cells
  • Methadone / pharmacology*
  • Mice
  • Morphine / pharmacology*
  • Naloxone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Phenanthridines / pharmacology
  • Protein Kinase C / antagonists & inhibitors
  • Rats
  • Receptors, Opioid, delta / antagonists & inhibitors*
  • Time Factors
  • Tumor Cells, Cultured


  • Alkaloids
  • Analgesics, Opioid
  • Benzophenanthridines
  • Enzyme Inhibitors
  • Narcotic Antagonists
  • Phenanthridines
  • Receptors, Opioid, delta
  • Colforsin
  • Naloxone
  • Enkephalin, Leucine-2-Alanine
  • Morphine
  • Cyclic AMP
  • chelerythrine
  • Protein Kinase C
  • Adenylyl Cyclases
  • Methadone