A descending inhibitory mechanism of nociception mediated by an evolutionarily conserved neuropeptide system in Drosophila
A descending inhibitory mechanism of nociception mediated by an evolutionarily conserved neuropeptide system in Drosophila
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果蝇进化上保守的神经肽系统介导的伤害感受的下降抑制机制
DOI：
10.1101/2022.03.08.483420
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Ken Honjo
中科院分区：
文献类型：
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作者：
Izumi Oikawa;Shu Kondo;Kao Hashimoto;Akiho Kashiwabara;Hiromu Tanimoto;Katsuo Furukubo-Tokunaga;Ken Honjo
伤害感觉是动物为了避免潜在的组织损伤刺激而发展起来的一种神经过程。在哺乳动物中，伤害感觉是由外周神经系统触发的，而中枢神经系统的调节是一个重要的过程，中枢神经系统的功能障碍与慢性疼痛的发病机制有广泛的关系。伤害感觉的外围机制在整个动物界基本上是保守的。然而，目前尚不清楚脑介导的调节是否也在非哺乳动物物种中保守。在这里，我们发现果蝇具有一种由神经肽drosulakinin （DSK）介导的来自大脑的伤害感觉下降抑制机制，DSK是胆囊收缩素（CCK）的同源物，在哺乳动物伤害感觉的下降控制中起重要作用。我们发现缺乏dsk或其受体的突变体对有毒的热敏感。通过结合遗传、行为、组织学和ca2 +成像分析，我们随后在单细胞分辨率上揭示了参与dskc介导的伤害感受调节的神经元，并确定了抑制伤害感受的dskc能下行神经元通路。本研究首次为非哺乳动物物种大脑中由进化保守的CCK系统介导的伤害感受的下行调节机制提供了证据，提出了下行抑制是一种古老的调节伤害感受的机制的可能性。
Nociception is a neural process that animals have developed to avoid potentially tissue-damaging stimuli. While nociception is triggered in the peripheral nervous system, its modulation by the central nervous system is a critical process in mammals, whose dysfunction has been extensively implicated in chronic pain pathogenesis. The peripheral mechanisms of nociception are largely conserved across the animal kingdom. However, it is unclear whether the brain-mediated modulation is also conserved in non-mammalian species. Here, we show that Drosophila has a descending inhibitory mechanism of nociception from the brain, mediated by the neuropeptide Drosulfakinin (DSK), a homolog of cholecystokinin (CCK) that plays an important role in the descending control of nociception in mammals. We found that mutants lacking dsk or its receptors are hypersensitive to noxious heat. Through a combination of genetic, behavioral, histological, and Ca 2+ imaging analyses, we subsequently revealed neurons involved in DSK-mediated nociceptive regulation at a single-cell resolution and identified a DSKergic descending neuronal pathway that inhibits nociception. This study provides the first evidence for a descending modulatory mechanism of nociception from the brain in a non-mammalian species that is mediated by the evolutionarily conserved CCK system, raising the possibility that the descending inhibition is an ancient mechanism to regulate nociception.