Cannabinoid and Vanilloid Effects of R(+)-Methanandamide in the Hemisected Meningeal Preparation

Abstract

The endogenous cannabinoid R(+)-methanandamide (mAEA) exerts differential anti- and pronociceptive effects by activating both cannabinoid (CB1) and vanilloid (TRPV1) receptors of nociceptive primary afferents. The significance of these effects in meningeal nociception was evaluated by modulation of calcitonin gene-related peptide (CGRP) release from meningeal afferents measured in an in vitro preparation of the hemisected rat skull. Temperature steps to 39 degrees C and 45 degrees C caused heat-dependent increases in CGRP release. One micromolar mAEA inhibited CGRP release at 32 degrees C but facilitated it at 45 degrees C. This effect was abolished in the presence of the TRPV1 receptor antagonist capsazepine. Lower doses of mAEA had no effect on basal or heat-evoked release. In the presence of the CB1 receptor antagonist SR141716 (0.2 microm) heat-stimulated increase in CGRP release was facilitated. CGRP release in the presence of SR141716 (0.2 microm) was further increased by adding mAEA at a concentration which had no effect on its own. These results confirm an opposing functional role for anandamide at CB1 and TRPV1 receptors on meningeal afferents.