Agonist of TRPM8 channel, menthol, facilitates the initiation of thermoregulatory responses to external cooling

The effects of activation of the cold and menthol sensitive TRPM8 ion channel on different thermoregulatory parameters (total oxygen consumption, carbon dioxide release, respiratory coefficient, vasoconstriction response of skin blood vessels and shivering) were studied in anaesthetized rats subjected to two types of external cooling—rapid and slow.Activation of TRPM8 by menthol even in thermoneutral conditions produced an increase in oxygen consumption and decrease in respiratory coefficient, which may be evidence of enhanced fat oxidation.Menthol, an agonist of the cold sensitive TRPM8 ion channel, decreased the temperature thresholds of all thermoregulatory responses induced by rapid and slow cooling without affecting the sequence of their initiation. Under menthol stimulation, there was enhancement of the first (urgent) phase of metabolic response at rapid cooling, and an increase in the skin blood vessel constrictor response at slow cooling. These changes lead to improved maintenance of core temperature when the organism is subjected to rapid or slow cooling.These data are compelling evidence for the contribution of TRPM8 ion channels to the formation of the thermal afferent signals in the initiation of cold defense responses. The effects of TRPM8 activation by menthol on metabolic parameters in thermoneutral conditions and under cooling suggest the continuous involvement of TRPM8 channel in regulation of total metabolism.