Nonthermal activation of transient receptor potential vanilloid-1 channels in abdominal viscera tonically inhibits autonomic cold-defense effectors
Nonthermal activation of transient receptor potential vanilloid-1 channels in abdominal viscera tonically inhibits autonomic cold-defense effectors
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DOI：
10.1523/jneurosci.1483-07.2007
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发表时间：
2007-07-11
影响因子：
5.3
通讯作者：
Romanovsky, Andrej A.
中科院分区：
文献类型：
--
作者：
Steiner, Alexandre A.;Turek, Victoria F.;Romanovsky, Andrej A.
瞬时受体电位香草酸（TRPV）1通道参与体温（T-b）调节尚未确定。本研究的目的是提供这种参与的决定性证据并确定其机制。我们合成了一种新的TRPV 1拮抗剂AMG 0347 [（E）-N-（7-羟基-5，6，7，8-四氢萘-1-基）-3-（2-（哌啶-1-基）6-（三氟甲基）吡啶-3-基）丙烯酰胺]，并对其进行了体外表征。然后我们发现这种药物是已知最有效的TRPV 1拮抗剂，可以增加大鼠和小鼠的T-b，并表明（通过使用基因敲除小鼠）AMG 0347的整个过热效应是TRPV 1依赖性的。AMG 0347诱导的体温过高是由两种主要的自主冷防御效应机制（尾部皮肤血管收缩和/或产热）之一或两者引起的，但不涉及寻温行为。在AMG 0347给药时，高热反应的幅度既不依赖于T-b也不依赖于尾部皮肤温度，因此表明AMG 0347诱导的高热是由非热因素阻断紧张性TRPV 1激活引起的。AMG 0347在脑（脑室内）或脊髓（鞘内）给药时引起体温过高的有效性并不比全身（静脉内）给药时更高，这表明作用部位为外周。然后，我们确定了腹膜内树脂毒素对TRPV 1通道的局部腹腔内脱敏可阻断对全身性AMG 0347的T-b反应;通过使用一系列综合功能试验确定脱敏程度。我们得出的结论是，通过尚未确定的非热因素对腹部内脏TRPV 1通道的紧张性激活可以抑制皮肤血管收缩和产热，从而对T-b产生抑制作用。
An involvement of the transient receptor potential vanilloid (TRPV) 1 channel in the regulation of body temperature (T-b) has not been established decisively. To provide decisive evidence for such an involvement and determine its mechanisms were the aims of the present study. We synthesized a new TRPV1 antagonist, AMG0347 [(E)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-3-(2-(piperidin-1-yl)6-(trifluoromethyl) pyridin-3-yl)acrylamide], and characterized it in vitro. We then found that this drug is the most potent TRPV1 antagonist known to increase T-b of rats and mice and showed ( by using knock-out mice) that the entire hyperthermic effect of AMG0347 is TRPV1 dependent. AMG0347-induced hyperthermia was brought about by one or both of the two major autonomic cold-defense effector mechanisms (tail-skin vasoconstriction and/or thermogenesis), but it did not involve warmth-seeking behavior. The magnitude of the hyperthermic response depended on neither T-b nor tail-skin temperature at the time of AMG0347 administration, thus indicating that AMG0347-induced hyperthermia results from blockade of tonic TRPV1 activation by nonthermal factors. AMG0347 was no more effective in causing hyperthermia when administered into the brain (intracerebroventricularly) or spinal cord (intrathecally) than when given systemically ( intravenously), which indicates a peripheral site of action. We then established that localized intra-abdominal desensitization of TRPV1 channels with intraperitoneal resiniferatoxin blocks the T-b response to systemic AMG0347; the extent of desensitization was determined by using a comprehensive battery of functional tests. We conclude that tonic activation of TRPV1 channels in the abdominal viscera by yet unidentified nonthermal factors inhibits skin vasoconstriction and thermogenesis, thus having a suppressive effect on T-b.