Transient receptor potential melastatin 8 (TRPM8) channels are involved in body temperature regulation.
Transient receptor potential melastatin 8 (TRPM8) channels are involved in body temperature regulation.
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DOI：
10.1186/1744-8069-8-36
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发表时间：
2012-05-09
期刊：
影响因子：
3.3
通讯作者：
Zhu DX
中科院分区：
文献类型：
--
作者：
Gavva NR;Davis C;Lehto SG;Rao S;Wang W;Zhu DX
瞬时受体电位阳离子通道亚家族M成员8（TRPM 8）在体外被低温激活，并已被证明在体内充当“低温传感器”。虽然已知这种“冷温度传感器”的激动剂，如薄荷醇和icilin，引起体温（Tb）的瞬时升高，但不知道TRPM8是否在Tb调节中起作用。由于TRPM8被认为是慢性疼痛治疗的潜在靶点，我们研究了TRPM8在Tb调节中的作用。我们表征了五种化学上不同的化合物（AMG 0635、AMG 2850、AMG 8788、AMG 9678和化合物496）作为TRPM 8的有效和选择性拮抗剂，并在植入无线电遥测探针的大鼠和小鼠中测试了它们对Tb的影响。研究中使用的所有五种拮抗剂均引起Tb的短暂降低（最大降低0.98°C）。由于体温调节是维持Tb约37°C的稳态过程，我们进一步评估了重复施用拮抗剂是否减弱Tb的降低。实际上，连续4天重复每日给予AMG 9678显示从第2天开始Tb降低幅度降低。本文报道的数据表明TRPM8通道在Tb调节中起作用。此外，在重复给药拮抗剂后Tb降低的幅度降低表明TRPM8在Tb维持中的作用可能不会对开发TRPM8拮抗剂作为治疗剂造成问题。
Transient receptor potential cation channel subfamily M member 8 (TRPM8) is activated by cold temperature in vitro and has been demonstrated to act as a ‘cold temperature sensor’ in vivo. Although it is known that agonists of this ‘cold temperature sensor’, such as menthol and icilin, cause a transient increase in body temperature (Tb), it is not known if TRPM8 plays a role in Tb regulation. Since TRPM8 has been considered as a potential target for chronic pain therapeutics, we have investigated the role of TRPM8 in Tb regulation. We characterized five chemically distinct compounds (AMG0635, AMG2850, AMG8788, AMG9678, and Compound 496) as potent and selective antagonists of TRPM8 and tested their effects on Tb in rats and mice implanted with radiotelemetry probes. All five antagonists used in the study caused a transient decrease in Tb (maximum decrease of 0.98°C). Since thermoregulation is a homeostatic process that maintains Tb about 37°C, we further evaluated whether repeated administration of an antagonist attenuated the decrease in Tb. Indeed, repeated daily administration of AMG9678 for four consecutive days showed a reduction in the magnitude of the Tb decrease Day 2 onwards. The data reported here demonstrate that TRPM8 channels play a role in Tb regulation. Further, a reduction of magnitude in Tb decrease after repeated dosing of an antagonist suggests that TRPM8’s role in Tb maintenance may not pose an issue for developing TRPM8 antagonists as therapeutics.
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