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Headache
2016[Oct]; 56
(9
): 1406-1417
PMID27634619
show ga
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.
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