ABSTRACT
Title
Ultrapotent effects of salvinorin A on LPS-stimulated murine macrophages and its antinflammatory action in vivo
Authors
G. Aviello1,2, F. Borrelli1,2, F. Guida3, B. Romano1,2, M. De Chiaro3,J.K. Zjawiony4, S. Maione3, A.A. Izzo1,2, R. Capasso1,2
1Dept. of Experimental Pharmacology, University of Naples Federico II, Naples, Italy; 2Endocannabinoid Research Group; 3Dept. of Experimental Medicine, Section of Pharmacology, The Second University of Naples, Naples, Italy; 4Dept. of Pharmacognosy, School of Pharmacy, University of Mississippi, University, USA.
1Dept. of Experimental Pharmacology, University of Naples Federico II, Naples, Italy; 2Endocannabinoid Research Group; 3Dept. of Experimental Medicine, Section of Pharmacology, The Second University of Naples, Naples, Italy; 4Dept. of Pharmacognosy, School of Pharmacy, University of Mississippi, University, USA.
Abstract
Background It is well known that the hallucinogenic compound salvinorin A, isolated from the Salvia divinorum plant, potently activates κ-opioid receptors (KORs) (Sheffler and Roth, 2003). Recently, other target(s) than the KORs, such as the cannabinoid CB1 receptor, have been proposed to explain the multiple pharmacological actions of salvinorin A (Capasso et al., 2008). Purpose Here, we have evaluated the effect of salvinorin A in lipopolysaccharide(LPS)-stimulated murine macrophages as well as in in vivo models of inflammation. Experimental approach Macrophages were obtained from mice by intraperitoneal injection of thioglycollate and thereafter activated by LPS (1 µg/ml). Nitrites were measured by DAN assay, TNF-α by ELISA, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), KOR and CB1 receptor expression by western blot. In vivo, the effect of salvinorin A was evaluated in mice using the LPS- and carrageenan-induced paw oedema. Key results Salvinorin A (0.1-10 pM) reduced LPS-stimulated nitrite and TNF-α levels as well as LPS-induced iNOS (but not COX-2) hyper-expression. The effect of salvinorin A on nitrite levels was reverted by the opioid antagonist naloxone, the KOR antagonist nor-binaltorphimine and by the CB1 antagonist rimonabant. Salvinorin A also prevented KOR and CB1 hyper-expression induced by LPS. In vivo, salvinorin A reduced - in a nor-binaltorphimine and rimonabant-sensitive manner - the paw oedema induced by both LPS and carrageenan. Conclusions Salvinorin A - via KORs and CB1 receptors - exerts ultrapotent actions in macrophages and also shows antinflammatory effects in vivo.
Sheffler and Roth (2003). Trends Pharmacol Sci. 24,107-9.
Capasso et al. (2008). Br J Pharmacol. 155,681-9.
Sheffler and Roth (2003). Trends Pharmacol Sci. 24,107-9.
Capasso et al. (2008). Br J Pharmacol. 155,681-9.