Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS

Gina F. Marrone, Steven G. Grinnell, Zhigang Lu, Grace C. Rossi, Valerie Le Rouzic, Jin Xu, Susruta Majumdar, Ying Xian Pan, Gavril W. Pasternak

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

The clinical management of severe pain depends heavily on opioids acting through mu opioid receptors encoded by the Oprm1 gene, which undergoes extensive alternative splicing. In addition to generating a series of prototypic seven transmembrane domain (7TM) G protein-coupled receptors (GPCRs), Oprm1 also produces a set of truncated splice variants containing only six transmembrane domains (6TM) through which selected opioids such as IBNtxA (3′-iodobenzoyl- 6β-naltrexamide) mediate a potent analgesiawithout many undesirable effects. Although morphine analgesia is independent of these 6TM mu receptor isoforms, we now show that the selective loss of the 6TM variants in a knockout model eliminates the analgesic actions of delta and kappa opioids and of α2-adrenergic compounds, but not cannabinoid, neurotensin, or muscarinic drugs. These observations were confirmed by using antisense paradigms. Despite their role in analgesia, loss of the 6TM variants were not involved with delta opioid-induced seizure activity, aversion to the kappa drug U50,488H, or α2-mediated hypolocomotion. These observations support the existence of parallel opioid and nonopioid pain modulatory systems and highlight the ability to dissociate unwanted delta, kappa1, and α2 actions from analgesia.

Original languageEnglish (US)
Pages (from-to)3663-3668
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number13
DOIs
StatePublished - Mar 29 2016
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Analgesia
  • GPCR
  • Morphine
  • Mu opioid receptor
  • Truncation

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