Methadone and heroin antinociception: Predominant δ-opioid-receptor responses in methadone-tolerant mice

Jodie J. Rady, Philip S. Portoghese, James M. Fujimoto

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Antinociceptive tail flick responses to heroin and 6-monoacetylmorphine mediated in the brain by μ-opioid receptor are switched by morphine pellet implantation to δ1- and δ2-opioid-receptors mediation, respectively. Present results showed that the μ-receptor response (inhibited by β-funaltrexamine) to methadone was changed by morphine pellet implantation to δ1 (inhibited by 7-benzylidenenaltrexone)- and δ2 (inhibited by naltriben)-opioid-receptor responses. Methadone pellet implantation likewise changed mediation from μ- to δ-opioid receptors for heroin and methadone but not for morphine (β-funaltrexamine continued to inhibit). Methadone μ action in the brain was linked through a descending system to activate spinal serotonin receptors (inhibited by methysergide), but this link was gone in the methadone-pellet-implanted group. In the latter group, the new δ1- and δ2-receptor responses were mediated by spinal GABAA (inhibited by bicuculline) and GABAB (inhibited by 2-hydroxysaclofen) receptors. These shifts in neuronal systems meant that μ receptors on a given neuron were not changed into δ receptors. Preliminary results showed that δ-agonist action for methadone was prevented from appearing by MK801, a NMDA-receptor antagonist, and did not occur in 129S6/SvEv mice which lack NMDA responsiveness. Could methadone maintenance treatment in humans uncover δ-agonist actions?

Original languageEnglish (US)
Pages (from-to)319-331
Number of pages13
JournalJapanese Journal of Pharmacology
Volume88
Issue number3
DOIs
StatePublished - 2002

Keywords

  • Antinociception
  • Chronic methadone
  • Heroin
  • Methadone
  • δ-Opioid receptor

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