Yang Chenyu, Yamaki Shanni, Jung Tyler, Kim Brian, Huyhn Ryan, McKemy David D
Neurobiology Section, Department of Biological Sciences; University of Southern California, Los Angeles, CA 90089.
Molecular and Computational Biology Graduate Program; University of Southern California, Los Angeles, CA 90089.
bioRxiv. 2023 Jan 23:2023.01.23.525238. doi: 10.1101/2023.01.23.525238.
The detection of environmental temperatures is critical for survival, yet inappropriate responses to thermal stimuli can have a negative impact on overall health. The physiological effect of cold is distinct among somatosensory modalities in that it is soothing and analgesic, but also agonizing in the context of tissue damage. Inflammatory mediators produced during injury activate nociceptors to release neuropeptides, such as CGRP and substance P, inducing neurogenic inflammation which further exasperates pain. Many inflammatory mediators induce sensitization to heat and mechanical stimuli but, conversely, inhibit cold responsiveness, and the identity of molecules inducing cold pain peripherally is enigmatic, as are the cellular and molecular mechanisms altering cold sensitivity. Here, we asked if inflammatory mediators that induce neurogenic inflammation via the nociceptive ion channels TRPV1 and TRPA1 lead to cold pain in mice. Specifically, we tested cold sensitivity in mice after intraplantar injection of lysophosphatidic acid (LPA) or 4-hydroxy-2-nonenal (4HNE), finding each induces cold pain that is dependent on the cold-gated channel TRPM8. Inhibition of either CGRP, substance P, or toll-like receptor 4 (TLR4) signaling attenuates this phenotype, and each neuropeptide produces TRPM8-dependent cold pain directly. Further, the inhibition of CGRP or TLR4 signaling alleviates cold allodynia differentially by sex. Lastly, we find that cold pain induced by inflammatory mediators and neuropeptides requires the neurotrophin artemin and its receptor GFRα3. These results demonstrate that tissue damage alters cold sensitivity via neurogenic inflammation, likely leading to localized artemin release that induces cold pain via GFRα3 and TRPM8.
The cellular and molecular mechanisms that generate pain are complex with a diverse array of pain-producing molecules generated during injury that act to sensitize peripheral sensory neurons, thereby inducing pain. Here we identify a specific neuroinflammatory pathway involving the ion channel TRPM8 and the neurotrophin receptor GFRα3 that leads to cold pain, providing select targets for potential therapies for this pain modality.
环境温度的检测对生存至关重要，但对热刺激的不适当反应会对整体健康产生负面影响。寒冷的生理效应在躯体感觉模式中是独特的，因为它具有舒缓和镇痛作用，但在组织损伤的情况下也会引起疼痛。损伤期间产生的炎症介质激活伤害感受器以释放神经肽，如降钙素基因相关肽（CGRP）和P物质，诱导神经源性炎症，进一步加剧疼痛。许多炎症介质会诱导对热和机械刺激的敏化，但相反，会抑制冷反应性，在外周诱导冷痛的分子身份尚不清楚，改变冷敏感性的细胞和分子机制也是如此。在这里，我们研究了通过伤害性离子通道TRPV1和TRPA1诱导神经源性炎症的炎症介质是否会导致小鼠冷痛。具体而言，我们在足底注射溶血磷脂酸（LPA）或4-羟基-2-壬烯醛（4HNE）后测试了小鼠的冷敏感性，发现每种物质都会诱导依赖于冷门控通道TRPM8的冷痛。抑制CGRP、P物质或Toll样受体4（TLR4）信号传导可减轻这种表型，并且每种神经肽都会直接产生依赖于TRPM8的冷痛。此外，抑制CGRP或TLR4信号传导会因性别而异减轻冷痛觉过敏。最后，我们发现炎症介质和神经肽诱导的冷痛需要神经营养因子artemin及其受体GFRα3。这些结果表明，组织损伤通过神经源性炎症改变冷敏感性，可能导致局部artemin释放，通过GFRα3和TRPM8诱导冷痛。
产生疼痛的细胞和分子机制很复杂，损伤期间会产生多种产生疼痛的分子，这些分子作用于使外周感觉神经元敏化，从而诱导疼痛。在这里，我们确定了一条涉及离子通道TRPM8和神经营养因子受体GFRα3的特定神经炎症途径，该途径会导致冷痛，为这种疼痛模式的潜在治疗提供了特定靶点。
