New perspectives on enigmatic vanilloid receptors

In spite of the rapid advances in our understanding of vanilloid-receptor pharmacology in the PNS, the function of vanilloid receptors in the brain has remained elusive. Recently, the endocannabinoid anandamide has been proposed to function as an endogenous agonist at the vanilloid receptor VRI. This is an exciting hypothesis because the localization of VRI overlaps with that of anandamide and its preferred cannabinoid receptor CB1 in various brain areas,The interaction of anandamide and/or related lipid metabolites with these two completely separate receptor systems in the brain clearly places VRI in a much broader role than pain perception. At a practical level, the overlapping ligand recognition properties of VRI and CB1 might be exploited by medicinal chemistry. For example, arvanil, a 'chimeric' ligand that combines structural features of capsaicin and anandamide, promises to be an interesting lead for new drugs that interact at both vanilloid and cannabinoid receptors.