Mediation of opioid analgesia by a truncated 6-transmembrane GPCR

J Clin Invest. 2015 Jul 1;125(7):2626-30. doi: 10.1172/JCI81070. Epub 2015 May 26.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alternative Splicing
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Exons
  • Gene Targeting
  • Methadone / pharmacology
  • Mice
  • Mice, Knockout
  • Morphine / pharmacology
  • Naltrexone / analogs & derivatives
  • Naltrexone / pharmacology
  • Pain / drug therapy
  • Pain / physiopathology
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / physiology
  • Protein Structure, Tertiary
  • Receptors, Opioid, mu / deficiency
  • Receptors, Opioid, mu / genetics*
  • Receptors, Opioid, mu / physiology*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism


  • Analgesics, Opioid
  • Oprm protein, mouse
  • Peptide Fragments
  • Receptors, Opioid, mu
  • Recombinant Proteins
  • iodobenzoylnaltrexamide
  • Naltrexone
  • Morphine
  • Methadone