title: Mediation of buprenorphine analgesia by a combination of traditional and truncated mu opioid receptor splice variants.
abstract: Buprenorphine has long been classified as a mu analgesic, although its high affinity for other opioid receptor classes and the orphanin FQ/nociceptin ORL1 receptor may contribute to its other actions. The current studies confirmed a mu mechanism for buprenorphine analgesia, implicating several subsets of mu receptor splice variants. Buprenorphine analgesia depended on the expression of both exon 1-associated traditional full length 7 transmembrane (7TM) and exon 11-associated truncated 6 transmembrane (6TM) MOR-1 variants. In genetic models, disruption of delta, kappa1 or ORL1 receptors had no impact on buprenorphine analgesia, while loss of the traditional 7TM MOR-1 variants in an exon 1 knockout (KO) mouse markedly lowered buprenorphine analgesia. Loss of the truncated 6TM variants in an exon 11 KO mouse totally eliminated buprenorphine analgesia. In distinction to analgesia, the inhibition of gastrointestinal transit and stimulation of locomotor activity were independent of truncated 6TM variants. Restoring expression of a 6TM variant with a lentivirus rescued buprenorphine analgesia in an exon 11 KO mouse that still expressed the 7TM variants. Despite a potent and robust stimulation of (35) S-GTPγS binding in MOR-1 expressing CHO cells, buprenorphine failed to recruit β-arrestin-2 binding at doses as high as 10 µM. Buprenorphine was an antagonist in DOR-1 expressing cells and an inverse agonist in KOR-1 cells. Buprenorphine analgesia is complex and requires multiple mu receptor splice variant classes but other actions may involve alternative receptors.
authors.affiliation: Department of Neurology and Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York.|Neuroscience Program, Weill Cornell Graduate School of Medical Sciences, New York, New York.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Grinnell
authors.affiliation: Department of Neuroscience and Cell Biology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey.
authors.forename: Michael
authors.initials: M
authors.lastname: Ansonoff
authors.affiliation: Department of Neurology and Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York.|Neuroscience Program, Weill Cornell Graduate School of Medical Sciences, New York, New York.
authors.forename: Gina F
authors.initials: GF
authors.lastname: Marrone
authors.affiliation: Department of Neurology and Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Neurology and Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York.|Neuroscience Program, Weill Cornell Graduate School of Medical Sciences, New York, New York.
authors.forename: Ankita
authors.initials: A
authors.lastname: Narayan
authors.affiliation: Department of Neurology and Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Psychology, Long Island University, Post Campus, Brookville, New York.
authors.forename: Grace
authors.initials: G
authors.lastname: Rossi
authors.affiliation: Department of Neurology and Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Susruta
authors.initials: S
authors.lastname: Majumdar
authors.affiliation: Department of Neurology and Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Ying-Xian
authors.initials: YX
authors.lastname: Pan
authors.affiliation: DiscoveRx Corporation, Fremont, California.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Bassoni
authors.affiliation: Department of Neuroscience and Cell Biology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey.
authors.forename: John
authors.initials: J
authors.lastname: Pintar
authors.affiliation: Department of Neurology and Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York.|Neuroscience Program, Weill Cornell Graduate School of Medical Sciences, New York, New York.
authors.forename: Gavril W
authors.initials: GW
authors.lastname: Pasternak
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002047:Buprenorphine / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D059225:Nociception; D011485:Protein Binding; D012326:RNA Splicing; D017450:Receptors, Opioid, mu / Q000235:genetics* / Q000378:metabolism; D000071560:beta-Arrestin 2 / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D000071560:beta-Arrestin 2; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D002047:Buprenorphine
keywords: 6TM; MOR-1; opioid