TRPA1 mediates the hypothermic action of acetaminophen
TRPA1 mediates the hypothermic action of acetaminophen
复制标题
DOI：
10.1038/srep12771
复制
发表时间：
2015-07-31
影响因子：
4.6
通讯作者：
Bevan, Stuart
中科院分区：
文献类型：
--
作者：
Gentry, Clive;Andersson, David A.;Bevan, Stuart
对乙酰氨基酚（Acetaminophen，APAP）是一种有效的解热镇痛药，也是最常用的镇痛药物之一.与解热非甾体类抗炎药不同，APAP除了解热作用外，还能降低体温。在这里，我们已经研究了负责APAP的低温活动的机制。皮下注射APAP，而非鞘内注射，引起野生型小鼠体温的剂量依赖性降低。用树脂毒素预处理的小鼠体温过低被消除，以破坏或去功能化外周TRPV 1表达末端，但对环加氧酶的抑制具有抵抗力。由于APAP诱发的体温降低在野生型和Trpv 1（-/-）小鼠中是相同的，并且通过给予最大有效剂量的TRPV 1拮抗剂而不降低，因此体温降低活性与TRPV 1无关。相反，TRPA 1拮抗剂抑制APAP诱导的体温降低，APAP对Trpa 1（-/-）小鼠的体温没有影响。在酵母诱导的发热模型中，给予APAP在野生型和Trpv 1（-/-）小鼠中引起明显的体温降低，但仅在Trpa 1（-/-）和Trpa 1（-/-）/Trpv 1（-/-）小鼠中恢复正常体温。我们的结论是TRPA 1介导APAP引起的体温降低。
Acetaminophen (APAP) is an effective antipyretic and one of the most commonly used analgesic drugs. Unlike antipyretic non-steroidal anti-inflammatory drugs, APAP elicits hypothermia in addition to its antipyretic effect. Here we have examined the mechanisms responsible for the hypothermic activity of APAP. Subcutaneous, but not intrathecal, administration of APAP elicited a dose dependent decrease in body temperature in wildtype mice. Hypothermia was abolished in mice pre-treated with resiniferatoxin to destroy or defunctionalize peripheral TRPV1-expressing terminals, but resistant to inhibition of cyclo-oxygenases. The hypothermic activity was independent of TRPV1 since APAP evoked hypothermia was identical in wildtype and Trpv1(-/-) mice, and not reduced by administration of a maximally effective dose of a TRPV1 antagonist. In contrast, a TRPA1 antagonist inhibited APAP induced hypothermia and APAP was without effect on body temperature in Trpa1(-/-) mice. In a model of yeast induced pyrexia, administration of APAP evoked a marked hypothermia in wildtype and Trpv1(-/-) mice, but only restored normal body temperature in Trpa1(-/-) and Trpa1(-/-)/Trpv1(-/-) mice. We conclude that TRPA1 mediates APAP evoked hypothermia.