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Biological indications of a novel "short" µ opiate receptor in domestic chicken.

ABSTRACT: Previous work from our laboratory has established that cellular signaling processes of endogenous morphine are mediated by cognate G protein coupled receptor (GPCR) proteins, designated µ(3) and µ(4) opiate receptors. µ(3) and µ(4) opiate receptors are structurally unique "short" 6 transmembrane helical (TMH) domain GPCRs that are selectively responsive to endogenous morphine, not to families of endogenous opioid peptides, and are uniquely coupled to activation of constitutive nitric oxide synthase (cNOS). Based on high resolution predictive measures, it appears likely that domestic poultry express a µ opiate receptor mRNA encoding potentially two novel GPCRs with similar biochemical characteristics as described for µ(3) and µ(4) opiate receptors as well as traditional µ(1) opioid receptors. The biological indications of these novel µ opiate receptors are discussed within the context of this short review.

SUBMITTER: Sheehan MH

PROVIDER: S-EPMC3284060 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Biological indications of a novel "short" µ opiate receptor in domestic chicken.

Sheehan Melinda H MH Kream Richard M RM Stefano George B GB

Archives of medical science : AMS 20100801 4

Previous work from our laboratory has established that cellular signaling processes of endogenous morphine are mediated by cognate G protein coupled receptor (GPCR) proteins, designated µ(3) and µ(4) opiate receptors. µ(3) and µ(4) opiate receptors are structurally unique "short" 6 transmembrane helical (TMH) domain GPCRs that are selectively responsive to endogenous morphine, not to families of endogenous opioid peptides, and are uniquely coupled to activation of constitutive nitric oxide synth ...[more]

PMID: 22371789

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Project description:BackgroundPregabalin and gabapentin improve neuropathic pain symptoms but there are emerging concerns regarding their misuse. This is more pronounced among patients with substance use disorder, particularly involving opioids. Co-ingestion of gabapentinoids with opioids is increasingly identified in opioid related deaths, however, the molecular mechanism behind this is still unclear. We have sought to determine whether pregabalin or gabapentin directly modulates acute μ receptor signaling, or μ receptor activation by morphine.MethodsThe effects of pregabalin and gabapentin were assessed in HEK 293 cells stably transfected with the human μ receptor. Their effect on morphine induced hyperpolarization, cAMP production and ERK phosphorylation were studied using fluorescent-based membrane potential assay, bioluminescence based CAMYEL assay and ELISA assay, respectively. Pregabalin/gabapentin effects on morphine-induced hyperpolarization were also investigated in AtT20 cells.ResultsPregabalin or gabapentin (1 µM, 100 µM each) did not activate the µ receptor or affect K channel activation or ERK phosphorylation produced by morphine. Neither drug affected the desensitization of K channel activation produced by prolonged (30 min) application of morphine. Gabapentin (1 µM, 100 µM) and pregabalin (1 µM) did not affect inhibition of forskolin-stimulated cAMP production by morphine. However, pregabalin (100 µM) potentiated forskolin mediated cAMP production, although morphine still inhibited cAMP levels with a similar potency to control.DiscussionPregabalin or gabapentin did not activate or modulate µ receptor signaling in three different assays. Our data do not support the hypothesis that gabapentin or pregabalin augment opioid effects through direct or allosteric modulation of the µ receptor. Pregabalin at a high concentration increases cAMP production independent of morphine. The mechanism of enhanced opioid-related harms from co-ingestion of pregabalin or gabapentin with opioids needs further investigation.

Dataset Information

Biological indications of a novel "short" µ opiate receptor in domestic chicken.

Publications

Biological indications of a novel "short" µ opiate receptor in domestic chicken.

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