Mediation of opioid analgesia by a truncated 6-transmembrane GPCR Journal Article


Authors: Lu, Z.; Xu, J.; Rossi, G. C.; Majumdar, S.; Pasternak, G. W.; Pan, Y. X.
Article Title: Mediation of opioid analgesia by a truncated 6-transmembrane GPCR
Abstract: The generation of potent opioid analgesics that lack the side effects of traditional opioids may be possible by targeting truncated splice variants of the μ-opioid receptor. μ-Opioids act through GPCRs that are generated from the Oprm1 gene, which undergoes extensive alternative splicing. The most abundant set of Oprm1 variants encode classical full-length 7 transmembrane domain (7TM) μ-opioid receptors that mediate the actions of the traditional μ-opioid drugs morphine and methadone. In contrast, 3-iodobenzoyl-6β-naltrexamide (IBNtxA) is a potent analgesic against thermal, inflammatory, and neuropathic pain that acts independently of 7TM μ-opioid receptors but has no activity in mice lacking a set of 6TM truncated μ-opioid receptor splice variants. Unlike traditional opioids, IBNtxA does not depress respiration or result in physical dependence or reward behavior, suggesting it acts through an alternative μ-opioid receptor target. Here we demonstrated that a truncated 6TM splice variant, mMOR-1G, can rescue IBNtxA analgesia in a μ-opioid receptor-deficient mouse that lacks all Oprm1 splice variants, ablating μ-opioid activity in these animals. Intrathecal administration of lentivirus containing the 6TM variant mMOR-1G restored IBNtxA, but not morphine, analgesia in Oprm1-deficient animals. Together, these results confirm that a truncated 6TM GPCR is both necessary and sufficient for IBNtxA analgesia.
Keywords: controlled study; exon; nonhuman; protein domain; mouse; opiate; animal experiment; animal model; alternative rna splicing; drug dependence; methadone; morphine; analgesia; neuropathic pain; g protein coupled receptor; mu opiate receptor; fentanyl; diamorphine; lentivirinae; virus expression; antibody labeling; buprenorphine; prostaglandin f2 alpha; ketazocine; priority journal; article; lentivirus infection
Journal Title: Journal of Clinical Investigation
Volume: 125
Issue: 7
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation  
Date Published: 2015-07-01
Start Page: 2626
End Page: 2630
Language: English
DOI: 10.1172/jci81070
PROVIDER: scopus
PUBMED: 26011641
PMCID: PMC4563690
DOI/URL:
Notes: Export Date: 3 August 2015 -- Source: Scopus
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MSK Authors
  1. Yingxian Pan
    123 Pan
  2. Zhigang Lu
    11 Lu
  3. Gavril W Pasternak
    379 Pasternak
  4. Jin   Xu
    57 Xu