Nociceptive afferent phenotyping reveals that transient receptor potential ankyrin 1 promotes cold pain through neurogenic inflammation upstream of the neurotrophic factor receptor GFRα3 and the menthol receptor transient receptor potential melastatin 8.
Nociceptive afferent phenotyping reveals that transient receptor potential ankyrin 1 promotes cold pain through neurogenic inflammation upstream of the neurotrophic factor receptor GFRα3 and the menthol receptor transient receptor potential melastatin 8.
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DOI：
10.1097/j.pain.0000000000002043
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发表时间：
2021-02-01
期刊：
影响因子：
7.4
通讯作者：
McKemy DD
中科院分区：
文献类型：
--
作者：
Yamaki S;Chau A;Gonzales L;McKemy DD
瞬时受体电位Melastatin 8离子通道（TRPM 8）是一种用于冷却化合物（如薄荷醇）的受体，是外周体感传入神经上的主要哺乳动物冷受体[35]。类似地，瞬时受体电位锚蛋白1（TRPA 1）通道是外源性和内源性刺激物和促痛剂的受体，但也是候选的有害冷换能器[47]。然而，TRPA 1或表达该通道的传入神经是否直接导致体内冷痛是有争议的[40]。具体而言，关于TRPA 1缺陷小鼠的行为表型的报告尚未得出结论，一些研究发现测试的急性寒冷行为存在缺陷，而其他研究则没有[5; 7; 24; 25; 27]。TRPA 1-空表达可降低与炎症性和神经性疼痛相关的冷超敏反应，体内外源性或内源性TRPA 1激动剂可增强冷反应性[16; 17; 19; 38; 50]。因此，在上调内源性通道调节剂的病理条件下，TRPA 1可以增加冷敏感性，这与其作为慢性疼痛的“看门人”的作用一致[6; 50] JRPA 1和TRPM 8是渗透小离子以及较大的带正电荷分子的非选择性阳离子通道[23; 44]。大阳离子通过这些通道的渗透已被用于选择性地将局部麻醉剂靶向特定的传入亚型，从而允许其在体内进行功能表型分析[44]。例如，带正电荷和细胞不渗透性钠通道阻滞剂QX-314（N-乙基利多卡因）与瞬时受体电位香草酸1（TRPV 1）（一种有毒的热门控通道）激动剂的共注射[14]已被广泛用于表型疼痛和瘙痒传入[8; 45]。类似地，我们已经证明，通过TRPM 8通道阻断神经传导可以抑制小鼠的寒冷和冷痛[33; 39]。
The Transient Receptor Potential Melastatin 8 ion channel (TRPM8), a receptor for cooling compounds such as menthol, is the principle mammalian cold receptor on peripheral somatosensory afferents [35]. Similarly, the Transient Receptor Potential Ankyrin 1 (TRPA1) channel is a receptor for exogenous and endogenous irritants and proalgesics, but is also a candidate noxious cold transducer [47]. However, if TRPA1 or the afferents expressing this channel directly contribute to cold pain in vivo is controversial [40]. Specifically, reports on the behavioral phenotype of TRPA1-deficient mice have been inconclusive with some studies finding deficits in the acute cold behaviors tested, whereas others have not [5; 7; 24; 25; 27]. Cold hypersensitivity associated with inflammatory and neuropathic pain are reduced in TRPA1-nulls, and cold responsiveness is potentiated by exogenous or endogenous TRPA1 agonists in vivo [16; 17; 19; 38; 50]. Thus, under pathological conditions that upregulate endogenous channel modifiers, TRPA1 may augment cold sensitivity, consistent with its role as a “gatekeeper” for chronic pain [6; 50].TRPA1 and TRPM8 are non-selective cation channels that permeate small ions, as well as larger positively-charged molecules [23; 44]. The permeation of large cations via these channels has been used to selectively target local anesthetics to specific afferents subtypes, allowing their functional phenotyping in vivo [44]. For example, co-injection of the positively-charged and cell-impermeant sodium channel blocker QX-314 (N-ethyl-lidocaine) with agonists for the Transient Receptor Potential Vanilloid 1 (TRPV1), a noxious heatgated channel [14], have been used extensively to phenotype pain and itch afferents [8; 45]. Similarly, we have shown that blocking nerve conduction via TRPM8 channels produces inhibition of cold and cold pain in mice [33; 39].
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通讯作者：
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