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Buprenorphine analgesia requires exon 11‐associated mu opioid receptor splice variants (659.11)
Author(s) -
Grinnell Steven,
Majumdar Susruta,
Ansonoff Michael,
Pintar John,
Pan YingXian,
Pasternak Gavril
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.659.11
Subject(s) - buprenorphine , exon , agonist , pharmacology , morphine , partial agonist , analgesic , opioid , μ opioid receptor , splice , opioid receptor , knockout mouse , receptor , ed50 , chemistry , medicine , gene , biochemistry
Buprenorphine is a potent analgesic with an attractive side effect profile. Although it is considered a partial mu opioid receptor (MOR) agonist and a weak partial agonist or antagonist at kappa opioid receptors, it also competes MOR exon 11‐associated IBNtxA binding with high affinity. We therefore sought to examine the roles of exon 11‐ and exon 1‐associated MOR splice variants in buprenorphine analgesia. Exon 11 knockout animals showed a profound loss of analgesia in the tail flick assay at doses over 300 times the analgesic ED50 in wildtype C57 controls, despite the fact that these animals have intact full length MOR‐1 receptors and other opioids such as morphine and methadone retain full analgesic efficacy. Furthermore, administration of a high dose of buprenorphine actually reversed morphine analgesia in these animals. In exon 1 or triple opioid knockout (MOR exon 1, DOR, and KOR) animals, analgesia was also significantly reduced relative to wildtype controls, suggesting that full buprenorphine analgesic efficacy requires both exon 11‐ and exon 1‐associated MOR splice variants, and that the pharmacology of buprenorphine is more complicated than previously believed. Grant Funding Source : Supported by DA02615, DA06241, DA07242 (GWP); DA013997 (YXP); and the PhRMA Foundation (SGG)