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

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 GABA_A (inhibited by bicuculline) and GABA_B (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?