TitleGenetic dissociation of morphine analgesia from hyperalgesia in mice.
Publication TypeJournal Article
Year of Publication2017
AuthorsMarrone GF, Le Rouzic V, Varadi A, Xu J, Rajadhyaksha AM, Majumdar S, Pan Y-X, Pasternak GW
JournalPsychopharmacology (Berl)
Date Published2017 Jun
KeywordsAlternative Splicing, Analgesia, Analgesics, Opioid, Animals, Dose-Response Relationship, Drug, Drug Tolerance, Female, Hyperalgesia, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Morphine, Pharmacogenomic Variants, Receptors, Opioid, mu

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.

Alternate JournalPsychopharmacology (Berl.)
PubMed ID28343361
PubMed Central IDPMC5520541
Grant ListT32 DA007242 / DA / NIDA NIH HHS / United States
R01 DA029122 / DA / NIDA NIH HHS / United States
R01 DA006241 / DA / NIDA NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R37 DA007242 / DA / NIDA NIH HHS / United States
R01 DA007242 / DA / NIDA NIH HHS / United States