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TRPM8 contributes to sex dimorphism by promoting recovery of normal sensitivity in a mouse model of chronic migraine.

ABSTRACT: TRPA1 and TRPM8 are transient receptor potential channels expressed in trigeminal neurons that are related to pathophysiology in migraine models. Here we use a mouse model of nitroglycerine-induced chronic migraine that displays a sexually dimorphic phenotype, characterized by mechanical hypersensitivity that develops in males and females, and is persistent up to day 20 in female mice, but disappears by day 18 in male mice. TRPA1 is required for development of hypersensitivity in males and females, whereas TRPM8 contributes to the faster recovery from hypersensitivity in males. TRPM8-mediated antinociception effects required the presence of endogenous testosterone in males. Administration of exogenous testosterone to females and orchidectomized males led to recovery from hypersensitivity. Calcium imaging and electrophysiological recordings in in vitro systems confirmed testosterone activity on murine and human TRPM8, independent of androgen receptor expression. Our findings suggest a protective function of TRPM8 in shortening the time frame of hypersensitivity in a mouse model of migraine.

SUBMITTER: Alarcon-Alarcon D

PROVIDER: S-EPMC9588003 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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TRPM8 contributes to sex dimorphism by promoting recovery of normal sensitivity in a mouse model of chronic migraine.

Alarcón-Alarcón David D Cabañero David D de Andrés-López Jorge J Nikolaeva-Koleva Magdalena M Giorgi Simona S Fernández-Ballester Gregorio G Fernández-Carvajal Asia A Ferrer-Montiel Antonio A

Nature communications 20221022 1

TRPA1 and TRPM8 are transient receptor potential channels expressed in trigeminal neurons that are related to pathophysiology in migraine models. Here we use a mouse model of nitroglycerine-induced chronic migraine that displays a sexually dimorphic phenotype, characterized by mechanical hypersensitivity that develops in males and females, and is persistent up to day 20 in female mice, but disappears by day 18 in male mice. TRPA1 is required for development of hypersensitivity in males and femal ...[more]

PMID: 36272975

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Project description: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.

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.

Dataset Information

TRPM8 contributes to sex dimorphism by promoting recovery of normal sensitivity in a mouse model of chronic migraine.

Publications

TRPM8 contributes to sex dimorphism by promoting recovery of normal sensitivity in a mouse model of chronic migraine.

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