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Neurosci."],"published-print":{"date-parts":[[2012,2,8]]},"abstract":"<jats:p>We studied<jats:italic>N<\/jats:italic>-(2-aminoethyl)-<jats:italic>N<\/jats:italic>-(4-(benzyloxy)-3-methoxybenzyl)thiophene-2-carboxamide hydrochloride (M8-B), a selective and potent antagonist of the transient receptor potential melastatin-8 (TRPM8) channel.<jats:italic>In vitro<\/jats:italic>, M8-B blocked cold-induced and TRPM8-agonist-induced activation of rat, human, and murine TRPM8 channels, including those on primary sensory neurons.<jats:italic>In vivo<\/jats:italic>, M8-B decreased deep body temperature (T<jats:sub>b<\/jats:sub>) in<jats:italic>Trpm8<\/jats:italic><jats:sup>+\/+<\/jats:sup>mice and rats, but not in<jats:italic>Trpm8<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice, thus suggesting an on-target action. Intravenous administration of M8-B was more effective in decreasing T<jats:sub>b<\/jats:sub>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<jats:sub>b<\/jats:sub>at either a constantly high or a constantly low ambient temperature (T<jats:sub>a<\/jats:sub>), but the same dose readily decreased T<jats:sub>b<\/jats:sub>if rats were kept at a high T<jats:sub>a<\/jats:sub>during the M8-B infusion and transferred to a low T<jats:sub>a<\/jats:sub>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 &lt;23\u00b0C, the magnitude of the M8-B-induced decrease in T<jats:sub>b<\/jats:sub>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.<\/jats:p>","DOI":"10.1523\/jneurosci.5606-11.2012","type":"journal-article","created":{"date-parts":[[2012,2,8]],"date-time":"2012-02-08T17:49:49Z","timestamp":1328723389000},"page":"2086-2099","source":"Crossref","is-referenced-by-count":222,"title":["Pharmacological Blockade of the Cold Receptor TRPM8 Attenuates Autonomic and Behavioral Cold Defenses and Decreases Deep Body Temperature"],"prefix":"10.1523","volume":"32","author":[{"given":"M. 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