Genetic dissociation of morphine analgesia from hyperalgesia in mice Journal Article
| Authors: | Marrone, G. F.; Le Rouzic, V.; Varadi, A.; Xu, J.; Rajadhyaksha, A. M.; Majumdar, S.; Pan, Y. X.; Pasternak, G. W. |
| Article Title: | Genetic dissociation of morphine analgesia from hyperalgesia in mice |
| 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. © 2017, Springer-Verlag Berlin Heidelberg. |
| Keywords: | controlled study; nonhuman; protein domain; mouse; gene; animal experiment; animal model; genetic association; genetic variability; immunological tolerance; alternative splicing; alternative rna splicing; immunomodulation; morphine; respiration depression; analysis of variance; analgesia; dissociation; hyperalgesia; naloxone; knockout; analgesic activity; reward; breathing; mor-1; mu opioid receptor; oprm1 gene; gpcr; mu opioid; truncated; male; female; priority journal; article; place preference; 6tm |
| Journal Title: | Psychopharmacology |
| Volume: | 234 |
| Issue: | 12 |
| ISSN: | 0033-3158 |
| Publisher: | Springer Germany |
| Date Published: | 2017-06-01 |
| Start Page: | 1891 |
| End Page: | 1900 |
| Language: | English |
| DOI: | 10.1007/s00213-017-4600-2 |
| PROVIDER: | scopus |
| PUBMED: | 28343361 |
| PMCID: | PMC5520541 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 July 2017 -- Source: Scopus |
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