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Salvinorin A analogues PR-37 and PR-38 attenuate compound 48/80-induced itch responses in mice.

ABSTRACT: The opioid system plays a crucial role in several physiological processes in the CNS and in the periphery. It has also been shown that selective opioid receptor agonists exert potent inhibitory action on pruritus and pain. In this study we examined whether two analogues of Salvinorin A, PR-37 and PR-38, exhibit antipruritic properties in mice.To examine the antiscratch effect of PR-37 and PR-38 we used a mouse model of compound 48/80-induced pruritus. In order to elucidate the mechanism of action of tested compounds, specific antagonists of opioid and cannabinoid receptors were used. The effect of PR-37 on the CNS was assessed by measuring motor parameters and exploratory behaviours in mice.PR-37 and PR-38, jnjected s.c., significantly reduced the number of compound 48/80-induced scratching behaviours in mice in a dose- and time-dependent manner. PR-38 was also active when orally administered. The antiscratch activity of PR-37 was blocked by the selective ? opioid receptor antagonist, nor-binaltorphimine, and that of PR-38 by the selective ? opioid receptor antagonist, ?-funaltrexamine.In conclusion, a novel framework for the development of new antipruritic drugs derived from salvinorin A has been validated.

SUBMITTER: Salaga M

PROVIDER: S-EPMC4556471 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Salvinorin A analogues PR-37 and PR-38 attenuate compound 48/80-induced itch responses in mice.

Salaga M M Polepally P R PR Zielinska M M Marynowski M M Fabisiak A A Murawska N N Sobczak K K Sacharczuk M M Do Rego J C JC Roth B L BL Zjawiony J K JK Fichna J J

British journal of pharmacology 20150714 17

<h4>Background and purpose</h4>The opioid system plays a crucial role in several physiological processes in the CNS and in the periphery. It has also been shown that selective opioid receptor agonists exert potent inhibitory action on pruritus and pain. In this study we examined whether two analogues of Salvinorin A, PR-37 and PR-38, exhibit antipruritic properties in mice.<h4>Experimental approach</h4>To examine the antiscratch effect of PR-37 and PR-38 we used a mouse model of compound 48/80-i ...[more]

PMID: 26040667

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Project description:Numerous inflammatory skin disorders display a high prevalence of itch. The Mas-related G protein coupled receptor X2 (MRGPRX2) has been shown to modulate itch by inducing non-IgE-mediated mast cell degranulation and the release of endogenous inducers of pruritus. Various substances collectively known as basic secretagogues, which include inflammatory peptides and certain drugs, can trigger MRGPRX2 and thereby induce pseudo-allergic reactions characterized by histamine and protease release as well as inflammation. Here, we investigated the capacity of an immunomodulatory single-stranded oligonucleotide (ssON) to modulate IgE-independent mast cell degranulation and, more specifically, its ability to inhibit the basic secretagogues compound 48/80 (C48/80)-and LL-37 in vitro and in vivo. We examined the effect of ssON on MRGPRX2 activation in vitro by measuring degranulation in a human mast cell line (LAD2) and calcium influx in MRGPRX2-transfected HEK293 cells. To determine the effect of ssON on itch, we performed behavioral studies in established mouse models and collected skin biopsies for histological analysis. Additionally, with the use of a rosacea mouse model and RT-qPCR, we investigated the effect on ssON on LL-37-induced inflammation. We reveal that both mast cell degranulation and calcium influx in MRGPRX2 transfected HEK293 cells, induced by the antimicrobial peptide LL-37 and the basic secretagogue C48/80, are effectively inhibited by ssON in a dose-dependent manner. Further, ssON demonstrates a capability to inhibit LL-37 and C48/80 activation in vivo in two mouse models. We show that intradermal injection of ssON in mice is able to block itch induced via C48/80 in a dose-dependent manner. Histological staining revealed that ssON inhibits acute mast cell degranulation in murine skin treated with C48/80. Lastly, we show that ssON treatment ameliorates LL-37-induced inflammation in a rosacea mouse model. Since there is a need for new therapeutics targeting non-IgE-mediated activation of mast cells, ssON could be used as a prospective drug candidate to resolve itch and inflammation in certain dermatoses.

Dataset Information

Salvinorin A analogues PR-37 and PR-38 attenuate compound 48/80-induced itch responses in mice.

Publications

Salvinorin A analogues PR-37 and PR-38 attenuate compound 48/80-induced itch responses in mice.

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