Androgenic TRPM8 activity drives sexual dimorphism in a murine model of chronic migraine

Abstract The mechanisms contributing to the high prevalence of chronic migraine in females are yet elusive. Here, we used a mouse model of nitroglycerin-induced chronic migraine that displays a sexual dimorphic phenotype and unveiled a role of TRPM8 as a testosterone receptor that provides antinociceptive resilience exclusively in males. Nitroglycerin induced similar mechanosensitivity to both sexes trough activation of TRPA1 channels, but triggered persistent hypersensitivity solely in females, as males readily recovered from the migraine crisis. Notably, we found that testosterone exerted an antinociceptive activity through its interaction with the TRPM8 channel. Downregulation of this protective mechanism in males led to persistent mechanical hypersensitivity, whereas administration of testosterone to females favoured their recovery. Thus, our findings reveal a novel protective function of TRPM8 through pre-clinical models of acute and chronic pain and highlights the interest of molecular solutions mimicking the pain-relieving activity of testosterone on TRPM8.