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 mu-opioid receptor are switched by morphine pellet implantation to delta(1)- and delta(2)-opioid-receptors mediation, respectively. Present results showed that the mu-receptor response (inhibited by beta-funaltrexamine) to methadone was changed by morphine pellet implantation to delta(1) (inhibited by 7-benzylidenenaltrexone-)and 52 (inhibited by naltriben)-opioid-receptor responses. Methadone pellet implantation likewise changed mediation from mu- to delta-opioid receptors for heroin and methadone but not for morphine (beta-funaltrexamine continued to inhibit). Methadone mu 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 delta(1)- and delta(2)-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 mu receptors on a given neuron were not changed into 6 receptors. Preliminary results showed that delta-agonist action for methadone was prevented from appearing by MK801, a NMDA-receptor antagonist, and did not occur in 12986/SvEv mice which lack NMDA responsiveness. Could methadone maintenance treatment in humans uncover delta-agonist actions?.