Methadone and heroin antinociception: predominant delta-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 delta1- and delta2-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 delta1 (inhibited by 7-benzylidenenaltrexone)- and delta2 (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 delta1- and delta2-receptor responses were mediated by spinal GABAA (inhibited by bicuculline) and GABAB (inhibited by 2-hydroxysaclofen) receptors. These shifts in neuronal systems meant that mu receptors on a given neuron were not changed into delta 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 129S6/SvEv mice which lack NMDA responsiveness. Could methadone maintenance treatment in humans uncover delta-agonist actions?
Rady
Jodie J
JJ
Research Service, VA Medical Center, Milwaukee, WI 53295, USA. jrady@mcw.edu
Portoghese
Philip S
PS
Fujimo
James M
JM
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D004361:Drug Tolerance; D003932:Heroin / Q000494:pharmacology*; D007276:Injections, Intraventricular; D008691:Methadone / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000187:drug effects*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors; D013045:Species Specificity
D000701:Analgesics, Opioid; D004343:Drug Implants; D016194:Receptors, N-Methyl-D-Aspartate; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D003932:Heroin; D008691:Methadone