TRPM8 and TRPM2 ion channels determine sex differences in thermal preference in mice

Several ion channels belonging to the large TRP family are activated either by increases or decreases in temperature, but it is unclear which of these potential thermosensors actually determine the sensation of temperature in the non-noxious thermal range, from approximately 20°C to approximately 40°C. Here we show that below 33°C, male cool preference is determined by TRPM8, whereas warm preference is mainly influenced by TRPM2. Female thermal preference is shifted to warmer temperatures by around 4°C when compared to males, consistent with warm shifts in the female activation ranges of both TRPM8 and TRPM2. Removal of testosterone causes a shift in male thermal preference towards female preference; conversely, female thermal preference is shifted towards male by injection of testosterone. Removing or injecting female hormones had no effect on thermal preference. We conclude that TRPM8 and TRPM2 are the main thermal detectors in the non-noxious range, and that testosterone is an important determinant of the difference in preference between males and females. KEY POINTS: In many mammals, including humans, females show a preference for warmer temperatures than males. Deletion of the trpm2 gene, coding for the warmth sensor TRPM2 in male mice shifted preference to warmer temperatures, showing that TRPM2 repels males from warm temperatures. Deletion or block of the cool sensor trpm8 in both males and females shifted preference to cooler temperatures, showing that TRPM8 repels mice from cooler temperatures. Deletion or block of trpv1 had no effect on non-noxious thermal preference. The results can be explained by a warm shift in females of activation ranges of both TRPM8 and TRPM2 when compared to males. Reducing testosterone in males caused a shift towards the female warm preference. Administering testosterone to females caused a shift towards the male cool preference. Female sex hormones had no effect. We conclude that TRPM8 and TRPM2 determine non-noxious thermal preference. Testosterone is an important determinant of the differences in thermal preference between males and females.