Females of many species, including humans, prefer warmer temperatures than males. New research in mice suggests that this is controlled by two thermal detectors in the body with differing sensitivity to warmth and cold.
The thermal detectors are two ion channels, which are proteins that control the entry of charged ions into nerve cells. How many ions are allowed to enter is influenced by the hormone, testosterone, which plays a role in determining how males and females sense temperature.
This is according to a new study published in The Journal of Physiology. Professor Peter McNaughton and Dr Bruno Vilar from the Wolfson Sensory, Pain and Regeneration Centre, part of the Institute of Psychiatry, Psychology and Neuroscience at King’s College London, UK, examined the molecular mechanisms driving the sex difference in thermal preference over a temperature range of 20-40°C.
The preference for warmth or cool is driven by thermally sensitive ion channels of the TRP (Transient receptor potential) family, which are found in the nerve endings of specialised neurons that detect physical and chemical changes in the external environment. The TRPM2 ion channel is sensitive to warmth, and the TRPM8 is sensitive to cold. “Other research groups have shown that coolness is detected by TRPM8, while we found some time ago that TRPM2 detects warmth,” says Peter McNaughton, Professor in Pharmacology at King’s College London.
Professor McNaughton and Dr Vilar identified a difference in molecular signalling between male and female mice. “Both TRPM2 and TRPM8 behave differently between males and females. The thermal ranges of activation of both are shifted towards warmer temperatures in females,” says Professor McNaughton.
It is this temperature shift that causes the difference in how males and female mice sense and react to temperature. There is also a hormonal basis. Professor McNaughton adds, “The shift is mainly, but not entirely, driven by testosterone, while the female sex hormones played no role in thermal preference in mice.”
There was a 4°C temperature difference in thermal preference between male and female mice. Male mice preferred 32°C, while female mice preferred a warmer 36°C. Similar sex differences have been reported in other mammalian species, including in humans, where human males prefer 22°C and females prefer a temperature of 25°C.
Female mice have lower testosterone levels than male mice. Reducing testosterone in male mice caused a shift towards the female warm preference. Increasing testosterone levels in female mice caused a shift towards the male cool preference, with females showing an enhanced aversion to heat.
To test thermal preference in this work, two adjacent metal plates were set at different temperatures. One plate was maintained at a temperature of 33°C, and the temperature of the other plate was varied. Professor McNaughton and Dr Vilar monitored the movement of the mice to see which of the two plates the mice preferred to stand on. They investigated the roles of thermally activated ion channels in thermal sensations by either removing particular ion channels genetically, or by blocking them using selective drugs.
Genetic deletion of the warmth sensor TRPM2 shifted the preference in male mice to warmer temperatures, bringing them closer to the thermal preference of females. Genetic deletion, or pharmacological block, of the cold sensor TRPM8 shifted the preference in female mice to cooler temperatures, closer to the male preference. “Gene deletion and a pharmacological block using drugs are two completely different approaches. That both manipulations had the same effects showed that the effects were due to direct actions on the ion channels themselves, rather than other off-target effects,” says Professor McNaughton.
“It has long been known that in many mammals, including humans, females prefer a warmer environment than males. But we hadn’t yet been able to identify the molecular basis for the different thermal sensations in females and males, until now,” says Professor McNaughton, explaining the complexity in determining the underlying mechanisms behind the sex difference. “The physiological roles of ion channels in thermal sensation, and the TRP channels that are involved in particular, have been remarkably contentious.”
This research was based on a mild thermal range to determine the comfort temperature, a balance between what the body senses as ‘too warm’ or ‘too cool’. Separate ion channels detect painful heat, which trigger behaviours that protect the body from thermal damage, but painful stimuli were not used in this work.
Male mice avoided the 38°C plate, while females showed a strong preference for 38°C over 33°C. There was no difference in core temperature or skin surface temperature between males and females that might have explained this difference. Instead, the mice must use sensory information. In the setup that was used, the nerve endings in the skin of the paws are the main thermal sensors, which ultimately lead to the behavioural response to move to the preferred temperature zone.
Humans also have both of these ion channels, but this study did not test whether they work the same way in people.
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