| Full text | |
| Author(s): Show less - |
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]
Total Authors: 14
|
| Affiliation: | [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
Total Affiliations: 5
|
| Document type: | Journal article |
| Source: | JOURNAL OF NEUROSCIENCE; v. 32, n. 6, p. 2086-2099, FEB 8 2012. |
| Web of Science Citations: | 120 |
| Abstract | |
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) | |