In:
The Journal of Neuroscience, Society for Neuroscience, Vol. 32, No. 6 ( 2012-02-08), p. 2086-2099
Abstract:
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 (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.
Type of Medium:
Online Resource
ISSN:
0270-6474
,
1529-2401
DOI:
10.1523/JNEUROSCI.5606-11.2012
Language:
English
Publisher:
Society for Neuroscience
Publication Date:
2012
detail.hit.zdb_id:
1475274-8
SSG:
12
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