JPET #59808 Anandamide is able to inhibit trigeminal neurons using an in vivo model of trigeminovascular-mediated nociception

Arachidonylethanolamide (AEA or anandamide) is believed to be the endogenous ligand of the cannabinoid CB1 and CB2 receptors. CB1 receptors have been found localized on fibers in the spinal trigeminal tract and spinal trigeminal nucleus caudalis. Known behavioural effects of anandamide are anti-nociception, catalepsy, hypothermia and depression of motor activity, similar to ∆-tetrahydocannanbinol, the psychoactive constituent of cannabis. It may be a possible therapeutic target for migraine. In this study we looked at the possible role of the CB1 receptor in the trigeminovascular system, using intravital microscopy to study the effects of anandamide against various vasodilator agents. Anandamide was able to inhibit dural blood vessel dilation brought about by electrical stimulation by 50%, CGRP by 30%, capsaicin by 45% and nitric oxide by 40%. CGRP8-37 was also able to attenuate NOinduced dilation by 50%. The anandamide inhibition was reversed by the CB1 receptor antagonist, AM251. Anandamide also reduced the blood pressure changes caused by CGRP injection, this effect was not reversed by AM251. It would seem that anandamide acts both pre-synaptically, to prevent CGRP release from trigeminal sensory fibers, and post-synaptically to inhibit the CGRP-induced NO release in the smooth muscle of dural arteries. CB1 receptors appear to be involved in the NO/CGRP relationship that exists in causing headache and dural blood vessel dilation. It also seems that some of the blood pressure changes caused by anandamide are mediated by a non-cannabinoid receptor, as AM251 was unable to reverse these effects. It can be suggested that anandamide is tonically released to play some form of modulatory role in the trigeminovascular system. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on January 12, 2004 as DOI: 10.1124/jpet.103.059808 at A PE T Jornals on A ril 9, 2017 jpet.asjournals.org D ow nladed from