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J Neurochem. 2019 Sep 3. doi: 10.1111/jnc.14863. [Epub ahead of print]

Phosphorylation of unique C-terminal sites of the mu-opioid receptor variants 1B2 and 1C1 influences their Gs association following chronic morphine.

Author information

1
Department of Obstetrics and Gynecology, State University of New York, Downstate Medical Center, 450 Clarkson Ave, Brooklyn, New York, 11203, USA.

Abstract

We recently demonstrated in rat spinal cord that a regimen of escalating doses of systemic morphine, analogous to regimens used clinically for chronic pain management, selectively upregulates the mu-opioid receptor (MOR) splice variants MOR-1B2 and MOR-1C1 mRNA and functional protein. The current study investigated the potential relevance of upregulating MOR-1B2 and MOR-1C1 to the ability of chronic morphine to shift MOR signaling from predominantly Gi /Go inhibitory to Gs stimulatory. Specifically, we tested the hypotheses that chronic morphine induces phosphorylation of carboxyl terminal sites unique to MOR-1B2 and MOR-1C1, and that this phosphorylation is causally related to augmented association of these variants with Gs α. Hypotheses were validated by (1) abolition of the chronic morphine-induced increment in MOR-1C1 and MOR-1B2 association with Gs α by inhibitors of protein kinase A and Casein kinase 2, respectively; (2) failure of chronic morphine to augment MOR variant Gs α interactions in Chinese hamster ovary cells transiently transfected with either rat MOR-1C1 or MOR-1B2 in which targeted protein kinase A and Casein kinase 2 serine phosphorylation sites, respectively, were mutated to alanine; (3) abrogation of chronic morphine-induced augmented MOR Gs α association in spinal cord of male rats following intrathecal administration of dicer substrate small interfering RNAs targeting MOR-1B2/MOR-1C1 mRNA. The ability of chronic morphine to not only upregulate specific MOR variants but also their carboxyl terminal phosphorylation and consequent augmented association with Gs α may represent a novel component of opioid tolerance mechanisms, suggesting novel potential targets for tolerance abatement. This article is protected by copyright. All rights reserved.

KEYWORDS:

MOR-1B2; MOR-1C1; casein kinase 2; mu opioid receptor splice variants; opioid tolerance; protein kinase A

PMID:
31479519
DOI:
10.1111/jnc.14863

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