*4.5. TRP Channel Modulators for Acute Treatment of Migraine Attacks*

As an initial line of investigation, TRPV1 agonists were considered as potential analgesics to treat headaches. Intranasal applications of civamide and capsaicin were reported to alleviate headache pain during migraine attack [167,168]. However, in most patients these agents caused severe side effects, such as nasal burning and lacrimation, and thus impeded their clinical use for the treatment of acute migraine. Instead, TRP channels antagonists show more promise as a novel approach to prevent or treat acute migraine attacks. However, an initial clinical randomized trial conducted in 2009 showed that TRPV1 channel blockers failed to treat migraine attacks. In this study, the compound SB-705498 did not relieve headache pain for up to 24 h post-dose [169]. Although this outcome does not exclude a contribution of TRPV1 to migraine pathology, it indicates that selectively targeting TRPV1 alone is not sufficient for acute treatment of migraine attacks. Another explanation for the lack of success with TRPV1 channel blockers is that SB-705498 is largely ineffective in humans. Several other clinical trials using this compound showed no or poor efficacy for treating different conditions. Notably, SB-705498 did not relieve itching arising from histamine-induced pruritus, prevent coughing in refractory chronic cough, or alleviate symptoms elicited by cold, dry air in non-allergic rhinitis [170–172], despite documented involvement of TRPV1 in these disorders. To date, no other clinical trials using TRP channel antagonists have been performed for migraine, but numerous in vivo studies show their potential for the development of new therapeutic strategies. Indeed, in a recent study, two TRPV1 antagonists, JNJ-38893777 and JNJ-17203212, reduced or even completely abolished capsaicin-induced CGRP release from TG neurons in two different animal models of migraine [121]. These compounds, used alone or together with other blockers of important molecular players, could be promising pain relief medicines.

Interestingly, a new molecule, Compound 16-8, which specifically co-targets TRPV4 and TRPA1, was developed based on the TRPV4 antagonist, GSK205 [124]. Compound 16-8 was reported to inhibit both channels at sub-micromolar potency and also abolish formalin-induced trigeminal pain in an in vivo model. This suggests that dual inhibitors may be more effective in treating pain elicited by several molecular players, such as pain that occurs in headaches and migraine induced by irritant compounds. To date, no clinical study has focused on TRPV4. This may be due to limited research concerning TRPV4, and the fact that dual inhibition strategies have not yet been considered for the treatment of migraine. Moreover, although the contribution of ANO1 to pain mechanisms in TG neurons is not fully elucidated [96] and interactions between TRP channels and ANO1 await investigation in the TGVS, we contend that ANO1 in TG neurons likely behaves similarly to that seen in DRG neurons. Thus, simultaneous blockage of TRP and ANO1 channels has potential to provide strong pain relief from headache.

Although TRPM8 variants are associated with migraine susceptibility, whether therapeutic strategies that target this channel should be agonists or antagonists, is unclear. As such, additional information about the role of TRPM8 in migraine development is needed before new therapeutics that focus on this channel can be pursued.
