Role of TRPM8 in cold avoidance behaviors and brain activation during innocuous and nocuous cold stimuli

Transient receptor potential melastatin 8 (TRPM8) is a cold-sensing cation channel; however, its role in the transferal of information on peripheral cold sensation to the brain remains unclear. Therefore, we herein investigated cold avoidance behaviors and the neuronal activation of the hypothalamus and cerebral cortex in TRPM8 knockout (KO) mice to innocuous and nocuous cold stimuli. An innocuous cold stimulation at 15 °C decreased the duration of sleeping and increased that of rearing, climbing, and eating in WT mice, but it did not alter the duration of these behaviors in TRPM8 KO animals. The innocuous cold stimulation also increased the frequency of rearing, climbing, walking, and eating in WT mice, but it did not change that of these behaviors in TRPM8 KO animals. In contrast, a nocuous cold stimulation at 9 °C decreased the duration of sleeping and increased that of rearing and climbing in both WT and TRPM8 KO mice. The nocuous cold stimulation increased the frequency of rearing, climbing, and walking in WT and TRPM8 KO mice. Quantitative Fos immunohistochemistry showed that both innocuous and nocuous cold stimulations increased the number of Fos-positive neurons in temperature- and metabolism-associated hypothalamic regions in WT mice, but not in TRPM8 KO animals. The number of Fos-positive neurons was markedly increased in the primary motor and somatosensory cortices in WT and TRPM8 KO mice following the nocuous cold stimulation, but only increased in WT mice after the innocuous cold stimulation. Collectively, the present results indicate that TRPM8 plays a crucial role in activating autonomic hypothalamic neuronal circuits under innocuous and nocuous cold stimuli.