• J. Neurosci. · Feb 2012

    Comparative Study

    Pharmacological blockade of the cold receptor TRPM8 attenuates autonomic and behavioral cold defenses and decreases deep body temperature.

    • M Camila Almeida, Tamara Hew-Butler, Renato N Soriano, Sara Rao, Weiya Wang, Judy Wang, Nuria Tamayo, Daniela L Oliveira, Tatiane B Nucci, Prafulla Aryal, Andras Garami, Diana Bautista, Narender R Gavva, and Andrej A Romanovsky.
    • Systemic Inflammation Laboratory (FeverLab), Trauma Research, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013, USA.
    • J. Neurosci. 2012 Feb 8; 32 (6): 2086-99.

    AbstractWe 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 (T(b)) 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 T(b) 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 T(b) at either a constantly high or a constantly low ambient temperature (T(a)), but the same dose readily decreased T(b) if rats were kept at a high T(a) during the M8-B infusion and transferred to a low T(a) 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 T(b) 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.

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