Anandamide Is Able to Inhibit Trigeminal Neurons Using an in Vivo Model of Trigeminovascular-Mediated Nociception

Abstract

Arachidonylethanolamide (anandamide, AEA) is believed to be the endogenous ligand of the cannabinoid CB 1 and CB 2 receptors. CB 1 receptors have been found localized on fibers in the spinal trigeminal tract and spinal trigeminal nucleus caudalis. Known behavioral effects of anandamide are antinociception, catalepsy, hypothermia, and depression of motor activity, similar to ⌬ 9 -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 CB 1 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%, calcitonin gene-related peptide (CGRP) by 30%, capsaicin by 45%, and nitric oxide by 40%. CGRP 8 -37 was also able to attenuate nitric oxide (NO)-induced dilation by 50%. The anandamide inhibition was reversed by the CB 1 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 presynaptically, to prevent CGRP release from trigeminal sensory fibers, and postsynaptically to inhibit the CGRP-induced NO release in the smooth muscle of dural arteries. CB 1 receptors seem 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 noncannabinoid 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.

Endocannabinoids in Chronic Migraine: CSF Findings Suggest a System Failure

“…This inhibitory effect has been demonstrated in experimental settings where AEA was able to inhibit dural blood vessel dilation due either to electrical stimulation or to CGRP, capsaicin, or NO application. This effect was reversed by the CB(1) receptor antagonist AM251 (Akerman et al, 2004a).…”

“…AEA seems to act both presynaptically, to prevent CGRP release from trigeminal sensory fibers, and postsynaptically to inhibit the CGRP-induced nitric oxide (NO) release in the smooth muscle of dural arteries. AEA is tonically released to play some form of modulatory role in the trigeminovascular system (Akerman et al, 2004a). All these suggestions prompted us to test the hypothesis that the endogenous CB system may be dysfunctional in chronic migraine (CM), as in other chronic pain entities such as fibromyalgia and IBS.…”

Variants in the CNR1 gene predispose to headache with nausea in the presence of life stress

“…In human studies, the metabolism of endocannabinoids is increased in migraineurs (Cupini et al 2006) resulting in decreased endocannabinoid tone (Sarchielli et al 2007; Van der Schueren et al 2012). In addition, animal studies showed that AEA was able to diminish the activation of the trigeminovascular system in nitroglycerin‐induced migraine models (Akerman et al 2004; Greco et al 2010; Nagy‐Grocz et al 2015) through a CB1 receptor mediated mechanism (Akerman et al 2013). …”

Effects of Mandrax and Cannabis on the cellular function of chick embryonic neurons

“…While in contrast is shown to relieve the symptoms of glaucoma (Hollister, 1986 andRobson, 2001) and migraines (Akerman et al, 2003), has a positive effect in diseases such as Multiple Sclerosis (Hollister, 1986, Robson, 2001and Akerman et al, 2003),…”