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TRPM8 and Migraine.

ABSTRACT: 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.

SUBMITTER: Dussor G

PROVIDER: S-EPMC5335856 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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TRPM8 and Migraine.

Dussor Greg G Cao Yu-Qing YQ

Headache 20160916 9

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 ...[more]

PMID: 27634619

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Project description:BackgroundMigraine is a chronic neurovascular condition characterized by recurring attacks of pulsating headaches. Genome-wide association studies (GWAS) identified many potential loci associated with migraine. To check the association of polymorphisms of PRDM16 (rs2651899), LRP1 (rs11172113), and TRPM8 (rs10166942) with migraine, the first time a case-control study was conducted in understudied Pakistani population.MethodsThe study included 127 migraine patients (21 in migraine with aura and 106 with migraine without aura group) and 120 healthy control subjects from different areas of Punjab, Pakistan. Blood samples were collected from all the participants, and DNA was isolated from the lymphocytes by the modified organic method. Sanger's sequencing was done for PRDM16 (rs2651899), LRP1 (rs11172113), and TRPM8 (rs10166942) in all the samples to check the genotype. Logistic regression analysis was done using SPSS 20.0 to check the association of these SNPs with migraine susceptibility.ResultsWe found statistically significant differences between case and control group for PRDM16 (rs2651899) at genotypic level (p < 0.001), allelic level (p < 0.001; OR 3.088; 95% CI 2.082-4.579) and for dominant model (p < 0.001; OR 5.437; 95% CI 3.112-9.498). The major findings of this study suggested that PRDM16 rs2651899 is strongly associated with migraine in overall and subgroup analysis of genotypes. LRP1 (rs11172113) showed significant association with migraine except in subgroup comparison. A similar trend of association was found for TRPM8 (rs10166942) however, significant association was found only at the allelic level but no significant difference was seen at the genotypic level between case and control. One novel mutation c.67 + 4436_67 + 4438delA was also identified in the current study near LRP1 (rs11172113) polymorphic site.ConclusionIn this first-ever replication report from Pakistan, PRDM16 (rs2651899) was found as a potential genetic marker in migraine susceptibility while LRP1 (rs11172113) and TRPM8 (rs10166942) showed partial association in subgroup analysis.

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TRPM8 and Migraine.

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TRPM8 and Migraine.

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