M Salaga1, P R Polepally2, M Zielinska1, M Marynowski1, A Fabisiak1, N Murawska1, K Sobczak1, M Sacharczuk3, J C Do Rego4, B L Roth5, J K Zjawiony2, J Fichna1. 1. Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland. 2. Department of BioMolecular Sciences, Division of Pharmacognosy and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS, USA. 3. Department of Molecular Cytogenetic, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Jastrzebiec, Poland. 4. Platform of Behavioural Analysis (SCAC), Institute for Research and Innovation in Biomedicine (IRIB), Faculty of Medicine & Pharmacy, University of Rouen, Rouen Cedex, France. 5. Department of Pharmacology, Division of Chemical Biology and Medicinal Chemistry, Medical School, NIMH Psychoactive Drug Screening Program, University of North Carolina, Chapel Hill, NC, USA.
Abstract
BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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 κ opioid receptor antagonist, nor-binaltorphimine, and that of PR-38 by the selective μ opioid receptor antagonist, β-funaltrexamine. CONCLUSION AND IMPLICATIONS: In conclusion, a novel framework for the development of new antipruritic drugs derived from salvinorin A has been validated.
BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: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 κ opioid receptor antagonist, nor-binaltorphimine, and that of PR-38 by the selective μ opioid receptor antagonist, β-funaltrexamine. CONCLUSION AND IMPLICATIONS: In conclusion, a novel framework for the development of new antipruritic drugs derived from salvinorin A has been validated.
Authors: Yong Chen; Quan Fang; Zilong Wang; Jennifer Y Zhang; Amanda S MacLeod; Russell P Hall; Wolfgang B Liedtke Journal: J Biol Chem Date: 2016-03-09 Impact factor: 5.157
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