The TRPA1 channel in migraine mechanism and treatment

Abstract

Migraine remains an elusive and poorly understood disease. The uncertainty is reflected by the currently unsatisfactory acute and prophylactic treatments for this disease. Genetic and pharmacological information points to the involvement of some transient receptor potential (TRP) channels in pain mechanisms. In particular, the TRP vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) channels seem to play a major role in different models of pain diseases. Recent findings have underscored the possibility that TRP channels expressed in the nerve terminals of peptidergic nociceptors contribute to the migraine mechanism. Among this channel subset, TRPA1, a sensor of oxidative, nitrative and electrophilic stress, is activated by an unprecedented series of irritant and pain-provoking exogenous and endogenous agents, which release the pro-migraine peptide, calcitonin gene-related peptide, through this neuronal pathway. Some of the recently identified TRPA1 activators have long been known as migraine triggers. Furthermore, specific analgesic and antimigraine medicines have been shown to inhibit or desensitize TRPA1 channels. Thus, TRPA1 is emerging as a major contributing pathway in migraine and as a novel target for the development of drugs for pain and migraine treatment.

Keywords: calcitonin gene-related peptide (CGRP); headache; migraine; neurogenic inflammation; neuropathic pain; oxidative stress; sensitization; thermoTRP; transient receptor potential ankyrin 1 (TRPA1).

Figure 1

Schematic representation of the activity of several agents (drugs, herbal medicines, endogenous and exogenous compounds), which, by targeting the TRPA1 channel, may positively or negatively affect the migraine attack via the release of CGRP and SP from peripheral and central endings of trigeminal neurons. (A) Some agents may behave as partial agonists or after an initial activation may lead to a profound and enduring channel desensitization. Both mechanisms by inhibiting CGRP release may eventually ameliorate migraine and cluster headache attacks. (B) In contrast, agonists of the TRPA1, by channel stimulation and the ensuing release of neuropeptide, may trigger migraine and cluster headache attacks.