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First published on October 26, 2007; DOI: 10.1124/mol.107.041863

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Received for publication September 18, 2007.
Revised October 26, 2007.
Accepted for publication October 26, 2007.

INHIBITION OF HUMAN NEUTROPHIL CHEMOTAXIS BY ENDOGENOUS CANNABINOIDS AND PHYTOCANNABINODS: EVIDENCE FOR A SITE DISTINCT FROM CB1 AND CB2

Douglas McHugh 1, Carolyn Tanner 2, Raphael Mechoulam 3, Roger G Pertwee 2, Ruth A Ross 2*

1 Indiana University 2 University of Aberdeen 3 Hebrew University of Jerusalem

* Address correspondence to: E-mail: r.ross{at}abdn.ac.uk

Abstract

Here we show a novel pharmacology for inhibition of human neutrophil migration by endocannabinoids, phytocannabinoids and related compounds. The endocannabinoids virodhamine and N-arachidonoyl dopamine are potent inhibitors of fMLP-induced migration of human neutrophils, with IC50 values of 0.2 and 8.80 nM respectively. The endocannabinoid, anandamide inhibits human neutrophil migration at nM concentrations in a bi-phasic manner. The phytocannabinoid, (-)-cannabidiol is a partial agonist, being ~ 40 fold more potent than (+)-cannabidiol; abnormal-cannabidiol is a full agonist. Furthermore, the abnormal-CBD analogue, O-1602 inhibits migration with an IC50 value of 33 nM. This reported profile of agonist efficacy and potency parallels with the pharmacology of the novel 'abnormal-cannabidiol' receptor or a related orphan GPCR, which are already known to modulate cell migration. Whilst having no effect alone, N-arachidonoyl L-serine attenuated inhibition of human neutrophil migration induced by anandamide, virodhamine and abnormal-CBD. Our data also suggest that there is cross-talk/negative co-operativity between the cannabinoid CB2 receptor and this novel target: CB2 receptor antagonists significantly enhance the inhibition observed with anandamide and virodhamine. This study reveals that certain endogenous lipids, phytocannabinoids and related ligands are potent inhibitors of human neutrophil migration and implicates a novel pharmacological target distinct from cannabinoid CB1 and CB2 receptors; this target is antagonised by the endogenous compound, N-arachidoloyl L-serine. Furthermore, our findings have implications for the potential pharmacological manipulation of elements of the endocannabinoid system for the treatment of various inflammatory conditions.


Key words: Cannabinoid, Gi family




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