British journal of pharmacology
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Comparative Study
Calcitonin gene-related peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat.
Calcitonin gene-related peptide (CGRP) is released into the cranial circulation of humans during acute migraine. To determine whether CGRP is involved in neurotransmission in craniovascular nociceptive pathways, we microiontophoresed onto neurons in the trigeminocervical complex and intravenously administered the CGRP receptor antagonists alpha-CGRP-(8-37) and BIBN4096BS. Cats were anaesthetised with alpha-chloralose, and using halothane during surgical preparation. ⋯ Intravenous BIBN4096BS resulted in a dose-dependent inhibition of trigeminocervical SSS-evoked activity (ED50 31 microg kg(-1)). The maximal effect observed within 30 min of administration. The data suggest that there are non-presynaptic CGRP receptors in the trigeminocervical complex that can be inhibited by CGRP receptor blockade and that a CGRP receptor antagonist would be effective in the acute treatment of migraine and cluster headache.
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Comparative Study
Anandamide acts as a vasodilator of dural blood vessels in vivo by activating TRPV1 receptors.
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. ⋯ 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.
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Comment
Calcitonin gene-related peptide (CGRP) antagonists: blockers of neuronal transmission in migraine.
The neuropeptide calcitonin gene-related peptide (CGRP) is a potent vasodilator that is contained in and released from sensory nerves. CGRP has been implicated in migraine, and the nonpeptide CGRP antagonist BIBN4096BS has been shown to be effective in clinical trials in migraine. To date, it has been largely assumed that the CGRP antagonist is effective due to its ability to block vasodilator activity. Goadsby and co-workers present data that now suggest that CGRP antagonists may also block neuronal transmission in migraine.