Effect of cannabinoids on CGRP release in the isolated rat lumbar spinal cord

•Capsaicin causes CGRP to be released from rat spinal cords.•This is suppressed by the TRPVR1 antagonist capsazapine.•Contrary to early reports, cannabinoid CB2 agonists do not inhibit CGRP release.•This result is consistent with a lack of functional CB2 receptors in the healthy spinal cord. Cannabinoids produce analgesia through a variety of mechanisms. It has been proposed that one mechanism is by modulating the release of CGRP in the spinal cord pain pathways. Previous studies have reported that cannabinoids, particularly CB2 receptor agonists, can modulate CGRP release in the isolated rat spinal cord. In our experiments, the TRPV1 agonist capsaicin evoked CGRP release and this was supressed by the TRPV1 antagonist capsazepine and by the opioid receptor agonist DAMGO. However, none of the cannabinoid receptor agonists that we tested were able to modulate evoked CGRP release; including WIN 55,212-2, methanandamide, and GW405833. These results question the role of spinal cord cannabinoid receptors in the regulation of CGRP signaling.