Cannabinoid Research
J
Pharmacol Exp Ther. 2006 Oct 3 [Epub ahead of print]
Cannabinoid (CB1) receptor activation inhibits
trigeminovascular neurons.
Akerman S, Holland P, Goadsby PJ.
Institute of Neurology, London.
Migraine is a common and disabling neurological disorder
that involves activation, or the perception of activation, of the
trigeminovascular system. Cannabinoid receptors are present in brain and have
been suggested to have an anti-nociceptive role. Here we determine the effect of
cannabinoid receptor activation on neurons with trigeminovascular nociceptive
input in the rat. Neurons in the trigeminocervical complex - trigeminal nucleus
caudalis (TNC) and dorsal horn of the C1 region- were studied using
extracellular electrophysiological techniques. Responses to both dural
electrical stimulation and cutaneous facial receptive field activation of the
ophthalmic division of the trigeminal nerve, and the effect of cannabinoid
agonists and antagonists were studied. Non-selective CB receptor activation,
with WIN55,212 (1 mgkg(-1), i.v) inhibited neuronal responses to A- (by 52%)and
C-fiber (by 44 %) afferents, an effect that was blocked by the CB1 receptor
antagonist, SR141716 (3 mgkg(-1), i.v), but not the CB2 receptor antagonist,
AM630 (3 mgkg(-1), i.v). Anandamide (10 mgkg(-1), i.v) was also able to inhibit
both A- and C-fiber elicited trigeminocervical complex (TCC) firing, but only
after TRPV1 receptor inhibition. Activation of cannabinoid receptors had no
effect on cutaneous receptive fields when recording from TCC neurons. The data
show that manipulation of CB1 receptors can affect the responses of trigeminal
neurons with A- and C-fiber inputs from the dura mater. This may be a direct
effect on neurons in the trigeminocervical complex itself, or an effect in
discrete areas of the brain that innervate these neurons. The data suggest
that CB receptors may have therapeutic potential in migraine, cluster headache
or other primary headaches, although the potential hazards of psychoactive
side-effects that accompany cannabinoid treatments may be complex to overcome.
PMID: 17018694
Br J Pharmacol. 2004 Aug;142(8):1354-60. Epub 2004 Jul 26.
Anandamide acts as a vasodilator of dural blood vessels in vivo by activating TRPV1 receptors.
Akerman S, Kaube H, Goadsby PJ.
Headache Group, Institute of Neurology, Queen Square, London, WC1N 3BG, U.K.
Migraine pathophysiology is believed to involve the release of
neuropeptides via the activation of trigeminal afferents that innervate
the cranial vasculature. Anandamide, the endogenous ligand to the
cannabinoid receptor, is able to inhibit neurogenic dural
vasodilatation, calcitonin gene-related peptide (CGRP)-induced and
nitric oxide-induced dural vessel dilation in the intravital microscopy
model. In an in vitro setting anandamide is also able to activate the
vanilloid type 1 (TRPV1) receptor and cause vasodilation, via the
release of CGRP. In this study we used intravital microscopy to study
whether anandamide behaves as a TRPV1 receptor agonist in the
trigeminovascular system. We examined if anandamide-induced dural
vasodilation involves CGRP release that can be reversed by the CGRP
receptor antagonist, CGRP(8-37), and whether like capsaicin the
anandamide effect could be reversed by the TRPV1 receptor antagonist,
capsazepine. Anandamide 1 (19+/-9%, n=12), 3 (29+/-5%, n=37), 5
(74+/-7%, n=13) and 10 mg kg(-1) (89+/-18%, n=6) was able to cause a
dose-dependent increase in dural vessel diameter. Capsazepine (3 mg
kg(-1), t(5)=6.2, P<0.05) and CGRP(8-37) (300 micrograms kg(-1),
t(6)=11.1, P<0.05) attenuated the anandamide-induced dural vessel
dilation when compared to control (Student's paired t-test). AM251 (3
mg kg(-1)), a cannabinoid type 1 (CB(1)) receptor antagonist, was
unable to reverse this anandamide-induced dilation. The study
demonstrates that anandamide acts as a TRPV1 receptor agonist in the
trigeminovascular system, activating TRPV1 receptors that promote CGRP
release and cause vasodilation independent of any action at the CB(1)
receptor. Anandamide has been shown previously to inhibit
trigeminovascular neurons and prevent vasodilation, through an action
at CB(1) receptors.
PMID: 15277315
J Pharmacol Exp Ther. 2004 Apr;309(1):56-63. Epub 2004 Jan 12.
Anandamide is able to inhibit trigeminal neurons using an in vivo model of trigeminovascular-mediated nociception.
Akerman S, Kaube H, Goadsby PJ.
Headache Group, Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
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 Delta(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.
PMID: 14718591
Note: Anandamide is a fatty-acid derived compound that possesses pharmacological properties similar to delta 9-THC, the psychoactive component in cannabis.
