%0 Journal Article %A M. Camila Almeida %A Tamara Hew-Butler %A Renato N. Soriano %A Sara Rao %A Weiya Wang %A Judy Wang %A Nuria Tamayo %A Daniela L. Oliveira %A Tatiane B. Nucci %A Prafulla Aryal %A Andras Garami %A Diana Bautista %A Narender R. Gavva %A Andrej A. Romanovsky %T Pharmacological Blockade of the Cold Receptor TRPM8 Attenuates Autonomic and Behavioral Cold Defenses and Decreases Deep Body Temperature %D 2012 %R 10.1523/JNEUROSCI.5606-11.2012 %J The Journal of Neuroscience %P 2086-2099 %V 32 %N 6 %X We studied N-(2-aminoethyl)-N-(4-(benzyloxy)-3-methoxybenzyl)thiophene-2-carboxamide hydrochloride (M8-B), a selective and potent antagonist of the transient receptor potential melastatin-8 (TRPM8) channel. In vitro, M8-B blocked cold-induced and TRPM8-agonist-induced activation of rat, human, and murine TRPM8 channels, including those on primary sensory neurons. In vivo, M8-B decreased deep body temperature (Tb) in Trpm8+/+ mice and rats, but not in Trpm8−/− mice, thus suggesting an on-target action. Intravenous administration of M8-B was more effective in decreasing Tb in rats than intrathecal or intracerebroventricular administration, indicating a peripheral action. M8-B attenuated cold-induced c-Fos expression in the lateral parabrachial nucleus, thus indicating a site of action within the cutaneous cooling neural pathway to thermoeffectors, presumably on sensory neurons. A low intravenous dose of M8-B did not affect Tb at either a constantly high or a constantly low ambient temperature (Ta), but the same dose readily decreased Tb if rats were kept at a high Ta during the M8-B infusion and transferred to a low Ta immediately thereafter. These data suggest that both a successful delivery of M8-B to the skin (high cutaneous perfusion) and the activation of cutaneous TRPM8 channels (by cold) are required for the hypothermic action of M8-B. At tail-skin temperatures <23°C, the magnitude of the M8-B-induced decrease in Tb was inversely related to skin temperature, thus suggesting that M8-B blocks thermal (cold) activation of TRPM8. M8-B affected all thermoeffectors studied (thermopreferendum, tail-skin vasoconstriction, and brown fat thermogenesis), thus suggesting that TRPM8 is a universal cold receptor in the thermoregulation system. %U https://www.jneurosci.org/content/jneuro/32/6/2086.full.pdf