Genetic dissociation of morphine analgesia from hyperalgesia in mice

Gina F. Marrone, Valerie Le Rouzic, Andras Varadi, Jin Xu, Anjali M. Rajadhyaksha, Susruta Majumdar, Ying Xian Pan, Gavril W. Pasternak

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Rationale: Morphine is the prototypic mu opioid, producing its analgesic actions through traditional 7 transmembrane domain (7TM) G-protein-coupled receptors generated by the mu opioid receptor gene (Oprm1). However, the Oprm1 gene undergoes extensive alternative splicing to yield three structurally distinct sets of splice variants. In addition to the full-length 7TM receptors, it produces a set of truncated variants comprised of only 6 transmembrane domains (6TM). Objectives: This study explored the relative contributions of 7TM and 6TM variants in a range of morphine actions. Methods: Groups of male and mixed-gender wild-type and exon 11 Oprm1 knockout mice were examined in a series of behavioral assays measuring analgesia, hyperalgesia, respiration, and reward in conditioned place preference assays. Results: Loss of the 6TM variants in an exon 11 knockout (E11 KO) mouse did not affect morphine analgesia, reward, or respiratory depression. However, E11 KO mice lacking 6TM variants failed to show morphine-induced hyperalgesia, developed tolerance more slowly than wild-type mice, and did not display hyperlocomotion. Conclusions: Together, our findings confirm the established role of 7TM mu receptor variants in morphine analgesia, reward, and respiratory depression, but reveal an unexpected obligatory role for 6TM variants in morphine-induced hyperalgesia and a modulatory role in morphine tolerance and dependence.

Original languageEnglish
Pages (from-to)1891-1900
Number of pages10
JournalPsychopharmacology
Volume234
Issue number12
DOIs
Publication statusPublished - Jun 1 2017

Keywords

  • 6TM
  • Alternative splicing
  • GPCR
  • KNOCKOUT
  • MOR-1
  • Mu opioid
  • Mu opioid receptor
  • Truncated

ASJC Scopus subject areas

  • Pharmacology

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  • Cite this

    Marrone, G. F., Le Rouzic, V., Varadi, A., Xu, J., Rajadhyaksha, A. M., Majumdar, S., Pan, Y. X., & Pasternak, G. W. (2017). Genetic dissociation of morphine analgesia from hyperalgesia in mice. Psychopharmacology, 234(12), 1891-1900. https://doi.org/10.1007/s00213-017-4600-2