Application of menthol to the skin of whole trunk in mice induces autonomic and behavioral heat-gain responses

Abstract

When ambient temperature is decreased in mammals, autonomic and behavioral heat-gain responses occur to maintain their core temperatures. However, what molecules in cutaneous sensory nerve endings mediate cooling-induced responses is unclear. Recently, transient receptor potential melastatin-8 (TRPM8) has been identified in cell bodies of sensory neurons as low-temperature and menthol-activated cation channel. We hypothesized that TRPM8 mediates cooling-induced autonomic and behavioral heat-gain responses. To activate TRPM8 specifically, we applied 1-10% menthol to the skin of whole trunk in mice instead of cooling and measured core temperatures and autonomic and behavioral heat-gain responses. Solvent of menthol (100% ethanol) was used as control. Significant elevation of core temperatures was observed between 20 and 120 min after menthol application. Pretreatment with diclofenac sodium, an antipyretic drug, did not affect this hyperthermia, indicating that the menthol-induced hyperthermia is not fever. Menthol application induced a rise in oxygen consumption, shivering-like muscle activity, tail skin vasoconstriction (autonomic responses), and heat-seeking behavior. All of them are typical heat-gain responses. These results support the hypothesis that TRPM8 mediates cooling-induced autonomic and behavioral heat-gain responses.

Intragastric Administration of TRPV1, TRPV3, TRPM8, and TRPA1 Agonists Modulates Autonomic Thermoregulation in Different Manners in Mice

“…Contrary to Tajino et al, menthol did not cause any heat diffusion effect. 34) This might be because Tajino et al utilized an experimental setup, dosage, administration route, and ambient temperature that were different from those used in our study.…”

“…Consistently with these results, it has been reported that menthol causes hyperthermia. 33,34) Moreover, Ding et al showed that a potent TRPM8 agonist, icillin, causes hyperthermia in rats. 35) These results suggest that activation of TRPM8 induces thermogenesis.…”

Shivering and tachycardic responses to external cooling in mice are substantially suppressed by TRPV1 activation but not by TRPM8 inhibition

“…Accordingly, a series of recent in vivo studies using pharmacological antagonism and/or genetic deletion have established that TRPM8 plays a significant role in most individual thermoregulatory responses to cold: behavioral thermoregulation, BAT activation, peripheral vasoconstriction, and total metabolic response to cold (1,2,6,8,17,33). TRPM8 was also implicated in shivering thermogenesis in two studies using menthol as a TRPM8 agonist, which, however, were not conclusive due to possible TRPM8-independent actions of menthol (15,18,21,34). Despite this caveat, these and other studies seemed to have formed a prevailing implicit view in the literature that TRPM8 is a "universal" cold sensor, insofar as it controls every physiological response to cold.…”

Central circuitries for body temperature regulation and fever

“…However, in a cold environment (10°C), TRPM8-deficient mice exhibit reduced activation of BAT thermogenesis and lowered body core temperature compared with wild-type mice (165). Application of menthol, which activates TRPM8, to the skin of wild-type mice evokes warm-seeking behavior, as well as cold-defensive, physiological responses, including BAT and shivering thermogenesis and cutaneous vasoconstriction (166). These findings indicate that TRPM8 plays a role in the sensation of environmental cooling that is required for eliciting feedforward colddefensive responses.…”