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Updated: Oct 1, 2026

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
Published on: July 29, 2014
Methadone and heroin antinociception: predominant delta-opioid-receptor responses in methadone-tolerant mice
Jodie J Rady1, Philip S Portoghese, James M Fujimo
1Research Service, VA Medical Center, Milwaukee, WI 53295, USA. jrady@mcw.edu
Abstract:
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?
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