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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.

SUBMITTER: Marrone GF

PROVIDER: S-EPMC5520541 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Genetic dissociation of morphine analgesia from hyperalgesia in mice.

Marrone Gina F GF Le Rouzic Valerie V Varadi Andras A Xu Jin J Rajadhyaksha Anjali M AM Majumdar Susruta S Pan Ying-Xian YX Pasternak Gavril W GW

Psychopharmacology 20170325 12

<h4>Rationale</h4>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).<h4>Objectives</h4>This ...[more]

PMID: 28343361

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Project description:Morphine and related compounds are the first line of therapy in the treatment of moderate to severe pain. Over time, individuals taking opioids can develop an increasing sensitivity to noxious stimuli, even evolving into a painful response to previously non-noxious stimuli (opioid-induced hyperalgesia; OIH). The mechanism underlying OIH is not well understood although complex intracellular neural mechanisms, including opioid receptor desensitization and down-regulation, are believed to be major mechanisms underlying OIH. However, OIH may also be associated with changes in gene expression. A growing body of evidence suggests that cellular exposure to mu agonists upregulate chemokines/receptors and recent work from our laboratory implicates chemokine upregulation in a variety of neuropathic pain behaviors. Here we characterized the degree to which chemokines/receptors signaling is increased in primary afferent neurons of the dorsal root ganglion (DRG) following chronic morphine sulfate treatment and correlated these changes with tactile hyperalgesic behavior in rodents. We demonstrate that mRNA expression of the chemokine, stromal-derived factor-1 (SDF1/CXCL12) is upregulated following morphine treatment in sensory neurons of the rat. The release of SDF1 was found to be constitutive when compared with the activity dependent release of the C-C chemokine, monocyte chemoattractant protein-1 (MCP1/CCL2) in a line of F11 neuroblastoma-sensory neuron hybrid cells. We further determined that there is pronounced CXCR4 expression in satellite glial cells and following morphine treatment, increased functional CXCR4 expression in sensory neurons of the DRG. Moreover, intraperitoneal administration of the specific CXCR4 antagonist, AMD3100, completely reversed OIH in the rat. Taken together; the data suggest that opioid-induced SDF1/CXCR4 signaling is central to the development of long lasting OIH and that receptor antagonists represent a promising novel approach to the management of the side effects associated with the use of opioids for chronic pain management.

Dataset Information

Genetic dissociation of morphine analgesia from hyperalgesia in mice.

Publications

Genetic dissociation of morphine analgesia from hyperalgesia in mice.

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