Pharmacological blockade of the cold receptor TRPM8 attenuates autonomic and behavioral cold defenses and decreases deep body temperature.
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.
Systemic Inflammation Laboratory (FeverLab), Trauma Research, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013, USA.
M Camila
MC
Almeida
Tamara
T
Hew-Butler
Renato N
RN
Soriano
Sara
S
Rao
Weiya
W
Wang
Judy
J
Wang
Nuria
N
Tamayo
Daniela L
DL
Oliveira
Tatiane B
TB
Nucci
Prafulla
P
Aryal
Andras
A
Garami
Diana
D
Bautista
Narender R
NR
Gavva
Andrej A
AA
Romanovsky
D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology*; D016466:CHO Cells; D002478:Cells, Cultured; D003080:Cold Temperature; D006224:Cricetinae; D003412:Cricetulus; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D004364:Pharmaceutical Preparations / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D012768:Shivering / Q000187:drug effects / Q000502:physiology*; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors* / Q000172:deficiency*; D013876:Thiophenes / Q000494:pharmacology
D004364:Pharmaceutical Preparations; D050053:TRPM Cation Channels; C000718063:TRPM8 antagonist M8-B; C492297:TRPM8 protein, mouse; D013876:Thiophenes