MacDonald Donald Iain, Balaji Rakshita, Chesler Alexander T
bioRxiv. 2025 Sep 11:2025.09.09.675093. doi: 10.1101/2025.09.09.675093.
Nociceptors are excitatory neurons that express a range of neuropeptides and have the essential role of detecting noxious mechanical, thermal and chemical stimuli. Ablating these neurons profoundly reduces responses to pain. Here we investigated how nociceptive information is transmitted by developing genetic approaches to suppress glutamate transmission and neuropeptide signaling, individually and in combination. Remarkably, many pain responses persisted in mice where either nociceptor glutamate or neuropeptide signaling was blocked. By contrast, mice lacking both glutamate and neuropeptide transmission in nociceptors displayed profound pain insensitivity closely matching the effects of cell ablation. Together our results establish a role for neuropeptides as pain transmitters and demonstrate redundancy in nociceptor signaling, resolving long-standing questions about how pain is communicated to the brain.
伤害感受器是兴奋性神经元，它们表达一系列神经肽，在检测有害的机械、热和化学刺激方面发挥着重要作用。消除这些神经元会显著降低对疼痛的反应。在这里，我们通过开发遗传方法来单独或联合抑制谷氨酸传递和神经肽信号传导，研究了伤害性信息是如何传递的。值得注意的是，在伤害感受器谷氨酸或神经肽信号传导被阻断的小鼠中，许多疼痛反应仍然存在。相比之下，伤害感受器中缺乏谷氨酸和神经肽传递的小鼠表现出深度疼痛不敏感，这与细胞消融的效果非常相似。我们的研究结果共同确立了神经肽作为疼痛传递者的作用，并证明了伤害感受器信号传导的冗余性，解决了关于疼痛如何传递到大脑的长期问题。
