Investigation of effects and mechanisms of transient receptor potential channels on calcitonin gene-related peptide release in ex-vivo rat meningeal preparations

Migraine is a disabling neurovascular disease. Duramater is regarded as origin of migraine. CGRP released from peripheral terminals of dural trigeminal sensory nerves plays key role in migraine pathophysiology by causing neurogenic inflammation. Transient-receptor-potential (TRP) and voltage-gated potassium (K+v) channels in dural afferents may have physiologic roles in migraine by modulating excitation threshold of the nerves and ultimately CGRP release. We investigated effects and mechanisms of TRPV1, TRPV4, TRPA1, TRPM8 and K+v channels on CGRP release in ex-vivo rat meningeal preparations. 39 adult wistar male rats were divided into 13 groups(n=6 hemiskull). Ex-vivo hemisected meningeal preparations were made. Preparations were treated with TRPV1(1 μM,capsaicin), TRPV4(100 μM,4αPDD), TRPA1(300 μM,Cinnamaldehyde) and TRPM8(300,μM Menthol) agonists and antagonists(10 μM capsazepine, 10 μM GSK-2193874, 50 μM HC-030031 and 10 μM AMTB) and K+v channel opener(10 μM,Retigabine). CGRP contents in superfusates were measured using ELISA. Data were analyzed with paired t-test. While agonists; TRPV1, TRPV4, TRPA1 and TRPM8 induced significantly CGRP release(P<0.05), these effects were prevented by antagonists capsazepine, GSK-2193874, HC-030031 and AMTB, respectively in meningeal preparations. K+v channel opener, Retigabine alone decreased basal CGRP release (P<0.05), and it prevented CGRP release induced by TRPV1, TRPV4, TRPA1 and TRPM8 receptors in meningeal preparations. Results revealed that TRPV1, TRPV4, TRPA1 and TRPM8 channels have physiologic roles for migraine and K+v channel opener has important roles to controlling nociceptive firing in migraine. Development of pharmacologic TRP receptor antagonists and K+v channel openers may be one of novel and alternative therapeutic approaches in migraine treatment, in the future.