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The ? opioid receptor agonist SNC80 selectively activates heteromeric ?-? opioid receptors.

ABSTRACT: Coexpressed and colocalized ?- and ?-opioid receptors have been established to exist as heteromers in cultured cells and in vivo. However the biological significance of opioid receptor heteromer activation is less clear. To explore this significance, the efficacy of selective activation of opioid receptors by SNC80 was assessed in vitro in cells singly and coexpressing opioid receptors using a chimeric G-protein-mediated calcium fluorescence assay, SNC80 produced a substantially more robust response in cells expressing ?-? heteromers than in all other cell lines. Intrathecal SNC80 administration in ?- and ?-opioid receptor knockout mice produced diminished antinociceptive activity compared with wild type. The combined in vivo and in vitro results suggest that SNC80 selectively activates ?-? heteromers to produce maximal antinociception. These data contrast with the current view that SNC80 selectively activates ?-opioid receptor homomers to produce antinociception. Thus, the data suggest that heteromeric ?-? receptors should be considered as a target when SNC80 is employed as a pharmacological tool in vivo.

SUBMITTER: Metcalf MD

PROVIDER: S-EPMC3399572 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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The δ opioid receptor agonist SNC80 selectively activates heteromeric μ-δ opioid receptors.

Metcalf Matthew D MD Yekkirala Ajay S AS Powers Michael D MD Kitto Kelley F KF Fairbanks Carolyn A CA Wilcox George L GL Portoghese Philip S PS

ACS chemical neuroscience 20120522 7

Coexpressed and colocalized μ- and δ-opioid receptors have been established to exist as heteromers in cultured cells and in vivo. However the biological significance of opioid receptor heteromer activation is less clear. To explore this significance, the efficacy of selective activation of opioid receptors by SNC80 was assessed in vitro in cells singly and coexpressing opioid receptors using a chimeric G-protein-mediated calcium fluorescence assay, SNC80 produced a substantially more robust resp ...[more]

PMID: 22860219

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Project description:Although participation of opioids in antinociception induced by cannabinoids has been documented, there is little information regarding the participation of cannabinoids in the antinociceptive mechanisms of opioids. The aim of the present study was to determine whether endocannabinoids could be involved in peripheral antinociception induced by activation of mu-, delta- and kappa-opioid receptors.Nociceptive thresholds to mechanical stimulation of rat paws treated with intraplantar prostaglandin E2 (PGE2, 2 microg) to induce hyperalgesia were measured 3 h after injection using an algesimetric apparatus. Opioid agonists morphine (200 microg), (+)-4-[(alphaR)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80) (80 microg), bremazocine (50 microg); cannabinoid receptor antagonists N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) (20-80 microg), 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl(4-methoxyphenyl) methanone (AM630) (12.5-100 microg); and an inhibitor of methyl arachidonyl fluorophosphonate (MAFP) (1-4 microg) were also injected in the paw.The CB1-selective cannabinoid receptor antagonist AM251 completely reversed the peripheral antinociception induced by morphine in a dose-dependent manner. In contrast, the CB2-selective cannabinoid receptor antagonist AM630 elicited partial antagonism of this effect. In addition, the administration of the fatty acid amide hydrolase inhibitor, MAFP, enhanced the antinociception induced by morphine. The cannabinoid receptor antagonists AM251 and AM630 did not modify the antinociceptive effect of SNC80 or bremazocine. The antagonists alone did not cause any hyperalgesic or antinociceptive effect.Our results provide evidence for the involvement of endocannabinoids, in the peripheral antinociception induced by the mu-opioid receptor agonist morphine. The release of cannabinoids appears not to be involved in the peripheral antinociceptive effect induced by kappa- and delta-opioid receptor agonists.

Dataset Information

The ? opioid receptor agonist SNC80 selectively activates heteromeric ?-? opioid receptors.

Publications

The δ opioid receptor agonist SNC80 selectively activates heteromeric μ-δ opioid receptors.

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