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In vitro, M8-B blocked cold- and TRPM8-agonist-induced activation in rat, human, and murine TRPM8 channels, including on primary sensory neurons. In vivo, M8-B reduced deep body temperature in TRPM8-sufficient animals, showed a peripheral delivery advantage, suppressed c-Fos in the lateral parabrachial nucleus, and required skin delivery plus cold-TRPM8 activation, consistent with TRPM8 as a universal cold receptor.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/pharmacological-blockade-of-the-cold-receptor-trpm8-attenuates-autonomic-and-behavioral-cold-defenses-and-decreases-deep-body-temperature/443819/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/pharmacological-blockade-of-the-cold-receptor-trpm8-attenuates-autonomic-and-behavioral-cold-defenses-and-decreases-deep-body-temperature/443819.png","ImageObject",300,407,{"name":92,"@type":93},"acoobca","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-05","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":34},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is M8-B and what does it target?","Question",{"text":112,"@type":113},"M8-B is a selective and potent antagonist of the TRPM8 channel.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does M8-B affect deep body temperature in animal models?",{"text":117,"@type":113},"M8-B decreases deep body temperature in TRPM8-expressing mice and rats, but not in TRPM8 knockout mice, indicating an on-target effect.",{"name":119,"@type":110,"acceptedAnswer":120},"Why is both skin delivery and cold activation of TRPM8 required for M8-B’s hypothermic action?",{"text":121,"@type":113},"A low intravenous dose does not change deep body temperature under constant ambient conditions unless animals receive M8-B while maintained at high temperature and then transferred to low temperature, implying effective delivery to the skin and activation of cutaneous TRPM8 by cold are both necessary.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},443819,1790845652,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":34,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},3985747870733,"https://ap-avatar.wpscdn.com/davatar_a8503ba1806abce46bf441b54a3ca4cd","Behavioral/Systems/Cognitive  \nPharmacological Blockade of the Cold Receptor TRPM8 Attenuates Autonomic and Behavioral Cold Defenses and Decreases Deep Body Temperature  \nM. Camila Almeida, 1,2 Tamara Hew-Butler, 1 Renato N. Soriano, 1 Sara Rao,3 Weiya Wang,3 Judy Wang,3 Nuria Tamayo,4 Daniela L. Oliveira, 1 Tatiane B. Nucci, 1 Prafulla Aryal,5 Andras Garami, 1 Diana Bautista,5 Narender R. Gavva,3 and AndrejA. Romanovsky1  \n1Systemic Inflammation Laboratory (FeverLab), Trauma Research, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona 85013, 2Natural and Humanities Sciences Center, Federal University of ABC, Santo Andr, SP 09210-170, Brazil, Departments of 3Neuroscience and 4Chemistry Research and Discovery, Amgen, Thousand Oaks, California 91320, and 5Department of Molecular and Cell Biology, University of California, Berkeley, California 94720  \nWe 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 (Tb ) 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 Tb 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 ofM8-B did not affect Tb ateithera constantly high ora constantly low ambient temperature(Ta), but the same dose readily decreased Tbifrats were kept ata high Ta during theM8-Binfusion and transferred toa low Ta immediately thereafter. These data suggest that both a successful delivery ofM8-Btothe skin(high cutaneous perfusion)and the activation ofcutaneousTRPM8channels(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 Tb 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.  \nIntroduction  \nDecreasing deep bodytemperature(Tb)can prolong life(Conti et al., 2006) and be life saving in many diseases. Mild therapeutic hypothermia is an effective treatment in cardiac arrest, neonatal  \nReceived Nov.7,2011;accepted Dec. 14,2011 .  \nAuthor contributions: M.C.A., N.T., D.B., N.R.G., andA.A.R. designed research;M.C.A., T.H.-B., R.N.S., S.R., W.W., J.W., N.T., D.L.O., T.B.N., P.A., A.G., and D.B. performed research; M.C.A., T.H.-B., R.N.S., S.R., W.W., J.W., D.L.O., T.B.N., P.A., A.G., D.B., N.R.G., andA.A.R. analyzed data;M.C.A., R.N.S., N.T., D.B., N.R.G., andA.A.R. wrote the paper.  \nThis work was supported by study agreements with Amgen (A.A.R.), National Institutes of Health Grants R01NS41233 (A.A.R.) and R01AR059385 (D.B.), and the So Paulo State Research Support Foundation Fellowship 07/50902-0 (R.N.S.) . We thank Peter Wettenstein for engineering assistance with the thermogradient studies; GustavoM. B. Souza for histological assistance;Kenneth D. Wild, James J. J. Treanor, and Mark H. Norman for their support for the antagonist development project; Nancy L. Romanovsky for graphics assistance; and Catherine M. Krall for editing this manuscript. R.N.S. was on leave from the Department of Physiology, Medical School of Ribeiro Preto, University of So Paulo, Ribeiro Preto, SP 14049-900, Brazil. A.G. was on leave from the Department of Pa","cbCaigB5hqt9eB1E","https://ap.wps.com/l/cbCaigB5hqt9eB1E","pdf",3281526,14,"English","# Introduction\n# Pharmacological targeting of TRPM8 (M8-B)\n# In vitro blockade of TRPM8 activation\n# In vivo effects on deep body temperature\n# Site of action and neural pathway evidence\n# Dependence on ambient temperature and delivery to skin\n# TRPM8 role across thermoeffectors","[{\"question\":\"What is M8-B and what does it target?\",\"answer\":\"M8-B is a selective and potent antagonist of the TRPM8 channel.\"},{\"question\":\"How does M8-B affect deep body temperature in animal models?\",\"answer\":\"M8-B decreases deep body temperature in TRPM8-expressing mice and rats, but not in TRPM8 knockout mice, indicating an on-target effect.\"},{\"question\":\"Why is both skin delivery and cold activation of TRPM8 required for M8-B’s hypothermic action?\",\"answer\":\"A low intravenous dose does not change deep body temperature under constant ambient conditions unless animals receive M8-B while maintained at high temperature and then transferred to low temperature, implying effective delivery to the skin and activation of cutaneous TRPM8 by cold are both necessary.\"}]","Pharmacological Blockade of the Cold Receptor TRPM8 Attenuates Autonomic and Behavioral Cold Defenses and Decreases Deep Body Temperature | PDF",1790705552,35]