Pharmacological blockade of TRPM8 ion channels alters cold and cold pain responses in mice.
Pharmacological blockade of TRPM8 ion channels alters cold and cold pain responses in mice.
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TRPM8离子通道的药理阻滞改变了小鼠的冷疼痛反应。
DOI：
10.1371/journal.pone.0025894
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
McKemy DD
中科院分区：
文献类型：
--
作者：
Knowlton WM;Daniels RL;Palkar R;McCoy DD;McKemy DD
TRPM 8（瞬时受体电位Melastatin-8）是哺乳动物外周神经系统中检测低温所必需的冷门控和薄荷醇门控离子通道。TRPM 8通道的功能是对无害冷、有害冷、损伤诱发的冷过敏、冷介导的镇痛和体温调节的行为反应所必需的。由于这些不同的作用，能够间接操纵TRPM 8功能以改变冷感觉神经元的兴奋性可能在临床上具有广泛的影响。在这里，我们研究了一种新的化合物，PBMC（1-苯乙基-4-（苄氧基）-3-甲氧基苄基（2-氨基乙基）氨基甲酸酯），它在体外以亚纳摩尔的亲和力强烈和选择性地抑制TRPM 8通道，如通过钙微量荧光测定法和电生理学所确定的。PBMC的作用对TRPM 8具有选择性，对感觉离子通道TRPV 1和TRPA 1没有观察到功能影响。PBMC通过将薄荷醇诱发的电流的电压依赖性移向正膜电位来改变TRPM 8门控。当对小鼠全身给药时，PBMC治疗在野生型动物中产生剂量依赖性体温降低，而TRPM 8敲除小鼠保持不受影响。这种低体温反应在较低剂量下减少，而对蒸发冷却的反应仍然显着减弱。最后，全身性PBMC也减少了炎症和神经损伤疼痛模型中的冷超敏反应，但对奥沙利铂诱导的神经性冷超敏反应无效，尽管我们发现TRPM 8是这种病理学的冷相关症状所必需的。因此，PBMC是一种有吸引力的化合物，其用作配制高度特异性和有效的TRPM 8拮抗剂的模板，所述TRPM 8拮抗剂将在体外和体内都具有效用。
TRPM8 (Transient Receptor Potential Melastatin-8) is a cold- and menthol-gated ion channel necessary for the detection of cold temperatures in the mammalian peripheral nervous system. Functioning TRPM8 channels are required for behavioral responses to innocuous cool, noxious cold, injury-evoked cold hypersensitivity, cooling-mediated analgesia, and thermoregulation. Because of these various roles, the ability to pharmacologically manipulate TRPM8 function to alter the excitability of cold-sensing neurons may have broad impact clinically. Here we examined a novel compound, PBMC (1-phenylethyl-4-(benzyloxy)-3-methoxybenzyl(2-aminoethyl)carbamate) which robustly and selectively inhibited TRPM8 channels in vitro with sub-nanomolar affinity, as determined by calcium microfluorimetry and electrophysiology. The actions of PBMC were selective for TRPM8, with no functional effects observed for the sensory ion channels TRPV1 and TRPA1. PBMC altered TRPM8 gating by shifting the voltage-dependence of menthol-evoked currents towards positive membrane potentials. When administered systemically to mice, PBMC treatment produced a dose-dependent hypothermia in wildtype animals while TRPM8-knockout mice remained unaffected. This hypothermic response was reduced at lower doses, whereas responses to evaporative cooling were still significantly attenuated. Lastly, systemic PBMC also diminished cold hypersensitivity in inflammatory and nerve-injury pain models, but was ineffective against oxaliplatin-induced neuropathic cold hypersensitivity, despite our findings that TRPM8 is required for the cold-related symptoms of this pathology. Thus PBMC is an attractive compound that serves as a template for the formulation of highly specific and potent TRPM8 antagonists that will have utility both in vitro and in vivo.
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