Involvement of exon 11-associated variants of the mu opioid receptor MOR-1 in heroin, but not morphine, actions.
Heroin remains a major drug of abuse and is preferred by addicts over morphine. Like morphine, heroin has high affinity and selectivity for mu-receptors, but its residual analgesia in exon 1 MOR-1 knockout mice that do not respond to morphine suggests a different mechanism of action. MOR-1 splice variants lacking exon 1 have been observed in mice, humans, and rats, raising the possibility that they might be responsible for the residual heroin and morphine-6beta-glucuronide (M6G) analgesia in the exon 1 knockout mice. To test this possibility, we disrupted exon 11 of MOR-1, which eliminates all of the variants that do not contain exon 1. Morphine and methadone analgesia in the exon 11 knockout mouse was normal, but the analgesic actions of heroin, M6G, and fentanyl were markedly diminished in the radiant heat tail-flick and hot-plate assays. Similarly, the ability of M6G to inhibit gastrointestinal transit was greatly diminished in these exon 11 knockout mice, whereas the ability of morphine was unchanged. These findings identify receptors selectively involved with heroin and M6G actions and confirm the relevance of the exon 11-associated variants and raise important issues regarding the importance of atypical truncated G-protein-coupled receptors.
Pan
Ying-Xian
YX
Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. pany@mskcc.org
Xu
Jin
J
Xu
Mingming
M
Rossi
Grace C
GC
Matulonis
Joshua E
JE
Pasternak
Gavril W
GW
D017398:Alternative Splicing / Q000187:drug effects; D000698:Analgesia; D000818:Animals; D005091:Exons / Q000235:genetics*; D005772:Gastrointestinal Transit / Q000187:drug effects; D018390:Gene Targeting; D003932:Heroin / Q000494:pharmacology*; D006579:Heterozygote; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D009154:Mutation / Q000235:genetics*; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000235:genetics*
C404943:Oprm protein, mouse; D017450:Receptors, Opioid, mu; D009270:Naloxone; D009271:Naltrexone; D003932:Heroin; C024524:beta-funaltrexamine; D009020:Morphine