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, 56 (9), 1406-1417

TRPM8 and Migraine


TRPM8 and Migraine

Greg Dussor et al. Headache.


Migraine is among the most common diseases on earth and one of the most disabling, the latter due in large part to poor treatment efficacy. Development of new therapeutics is dependent on the identification of mechanisms contributing to migraine and discovery of targets for new drugs. Numerous genome-wide association studies (GWAS) have implicated the transient receptor-potential M8 (TRPM8) channel in migraine. This channel is predominantly expressed on peripheral sensory neurons and is known as the sensor for cold temperature in cutaneous tissue but is also expressed on deep visceral afferents where cold is not likely a stimulus. Consequently, a number of alternative endogenous agonists have been proposed. Apart from its role in cold sensation, TRPM8 also contributes to cold allodynia after nerve injury or inflammation, and it is necessary for cooling/menthol-based analgesia. How it might contribute to migraine is less clear. The purpose of this review is to discuss the anatomical and physiological mechanisms by which meningeal TRPM8 may play a role in migraine as well as the potential of TRPM8 as a therapeutic target. TRPM8 is expressed on sensory afferents innervating the meninges, and these neurons are subject to developmental changes that may influence their contribution to migraine. As in viscera, meningeal TRPM8 channels are unlikely to be activated by temperature fluctuations and their endogenous ligands remain unknown. Preclinical migraine studies show that activation of meningeal TRPM8 by exogenous agonists can both cause and alleviate headache behaviors, depending on whether other meningeal afferents concurrently receive noxious stimuli. This is reminiscent of the fact that cold can trigger migraine in humans but menthol can also alleviate headache. We propose that both TRPM8 agonists and antagonists may be potential therapeutics, depending on how migraine is triggered in individual patients. In this regard, TRPM8 may be a novel target for personalized medicine in migraine treatment.

Keywords: TRP; dura; icilin; meninges; menthol; trigeminal.


Fig. 1
Fig. 1
TRPM8 activation in the dura can be pro- or anti-nociceptive. Panel A shows that activation of TRPM8-expressing fibers (blue) in the absence of other stimuli causes afferent signaling into the trigeminal nucleus caudalis (TNC), activation of second-order neurons that project into the brain, and ultimately to the perception of pain. Panel B shows that activation of TRPM8-expressing fibers (orange) in the presence of ongoing activation of other TG nociceptors (red) by stimuli such as inflammation can inhibit nociceptive signaling. The inhibition of nociceptive afferent signaling by TRPM8-expressing fibers can either be via direct inhibition of TG nociceptor central terminals (orange to red) or by activation of inhibitory TNC interneurons (yellow) that synapse onto nociceptor afferents or onto second-order TNC projection neurons. [Color figure can be viewed at]

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