Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
Mediation of opioid analgesia by a truncated 6-transmembrane GPCR
Zhigang Lu, … , Gavril W. Pasternak, Ying-Xian Pan
Zhigang Lu, … , Gavril W. Pasternak, Ying-Xian Pan
Published May 26, 2015
Citation Information: J Clin Invest. 2015;125(7):2626-2630. https://doi.org/10.1172/JCI81070.
View: Text | PDF
Brief Report Genetics Neuroscience Therapeutics

Mediation of opioid analgesia by a truncated 6-transmembrane GPCR

  • Text
  • PDF
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.

Authors

Zhigang Lu, Jin Xu, Grace C. Rossi, Susruta Majumdar, Gavril W. Pasternak, Ying-Xian Pan

×

Figure 3

Lentivirus rescue of IBNtxA analgesia.

Options: View larger image (or click on image) Download as PowerPoint
Lentivirus rescue of IBNtxA analgesia.
(A) Opioid analgesia. Analgesia w...
(A) Opioid analgesia. Analgesia was determined in groups of mice (n = 6–13) at the stated time. (*P < 0.0001 compared with week 0; ANOVA followed by Tukey). (B) IBNtxA cumulative dose–response curves were carried out in exon 1/exon 11 KO mice with lentivirus vector alone (n = 4), lenti–mMOR-1G (ED50 1.1 mg/kg [95% CI, 0.72–1.53], n = 18) and WT mice (ED50 0.42 mg/kg [95% CI, 0.29–0.58], n = 16). (C) Single doses of IBNtxA (2.5 mg/kg, s.c. n = 5), morphine (10 mg/kg, s.c. n = 7), fentanyl (0.08 mg/kg, s.c. n = 7), buprenorphine (1 mg/kg, s.c. n = 7), ketocyclazocine (2 mg/kg, s.c. n = 7), or levorphanol (0.8 mg/kg, s.c. n = 7) were administered to groups of either WT or exon 1/exon 11 KO mice infected with lenti–mMOR-1G. The mice were assessed for analgesia. Another group of mice received IBNtxA with levallorphan (2.5 mg/kg, s.c. n = 7). ANOVA shows that the IBNtxA group and the ketocyclazocine group were significantly different (*P < 0.001 and **P < 0.006 by ANOVA, respectively). The IBNtxA WT and lenti–mMOR-1G animals were not significantly different from each other but were different from both the exon 1/exon 11 KO alone and the lenti–mMOR‑1G/levallorphan groups (Tukey). Ketocyclazocine in WT and lenti–mMOR-1G were not significantly different from each other but were different from exon 1/exon 11 alone (Tukey).
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts