Pharmacological Blockade of the Cold Receptor TRPM8 Attenuates Autonomic and Behavioral Cold Defenses and Decreases Deep Body Temperature

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Almeida, M. Camila ^{[1, 2]} ; Hew-Butler, Tamara ^[1] ; Soriano, Renato N. ^[1] ; Rao, Sara ^[3] ; Wang, Weiya ^[3] ; Wang, Judy ^[3] ; Tamayo, Nuria ^[4] ; Oliveira, Daniela L. ^[1] ; Nucci, Tatiane B. ^[1] ; Aryal, Prafulla ^[5] ; Garami, Andras ^[1] ; Bautista, Diana ^[5] ; Gavva, Narender R. ^[3] ; Romanovsky, Andrej A. ^[1]

Afiliação do(s) autor(es)

^[1] St Josephs Hosp, System Inflammat Lab, FeverLab, Phoenix, AZ 85013 - USA

^[2] Fed Univ ABC, Nat & Humanities Sci Ctr, BR-09210170 Santo Andre, SP - Brazil

^[3] Amgen Inc, Dept Neurosci, Thousand Oaks, CA 91320 - USA

^[4] Amgen Inc, Dept Chem Res & Discovery, Thousand Oaks, CA 91320 - USA

^[5] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 - USA

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF NEUROSCIENCE; v. 32, n. 6, p. 2086-2099, FEB 8 2012.
• Citações Web of Science: 120

Resumo

We studied N-(2-aminoethyl)-N-(4-(benzyloxy)-3-methoxybenzyl)thiophene-2-carboxamid e 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 degrees 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. (AU)

• Processo FAPESP: 07/50902-0 - Estudo da via do oxido nitrico no locus coeruleus na eutermia e febre.
• Beneficiário: Renato Nery Soriano
• Modalidade de apoio: Bolsas no Brasil - Doutorado