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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DOI：
10.7554/elife.85760
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发表时间：
2023-06-13
期刊：
影响因子：
7.7
通讯作者：
Honjo K
中科院分区：
文献类型：
--
作者：
Oikawa I;Kondo S;Hashimoto K;Yoshida A;Hamajima M;Tanimoto H;Furukubo-Tokunaga K;Honjo K
伤害感受是动物为了避免潜在的组织损伤性刺激而形成的一种神经过程。虽然伤害感受是在周围神经系统中触发的，但中枢神经系统的调节是哺乳动物的一个关键过程，其功能障碍与慢性疼痛发病机制有广泛的关联。伤害感受的外围机制在整个动物界基本上是保守的。然而，目前尚不清楚大脑介导的调节在非哺乳动物物种中是否也保守。在这里，我们发现果蝇具有大脑伤害感受的下行抑制机制，由神经肽 Drosulfakinin (DSK) 介导，DSK 是胆囊收缩素 (CCK) 的同源物，在哺乳动物伤害感受的下行控制中发挥重要作用。我们发现缺乏 dsk 或其受体的突变体对有害热过敏。通过结合遗传、行为、组织学和 Ca2+ 成像分析，我们随后以单细胞分辨率揭示了参与 DSK 介导的伤害感受调节的神经元，并确定了抑制伤害感受的 DSKergic 下行神经元通路。这项研究提供了第一个证据，证明非哺乳动物物种的大脑伤害感受的下降调节机制是由进化上保守的 CCK 系统介导的，这提高了下降抑制是调节伤害感受的古老机制的可能性。避免伤害是动物生存的根本。称为伤害感受器的神经细胞可以检测潜在的损害，例如极端温度、尖锐物体和某些化学物质。在人类中，这种检测（称为伤害感受）会导致信号从伤害感受器通过脊髓传输到大脑，大脑将其视为疼痛。人类和啮齿动物等哺乳动物可以通过从大脑向脊髓发送信号来抑制疼痛，从而抑制伤害感受。这种自上而下的抑制过程被认为在调节哺乳动物的疼痛方面发挥着至关重要的作用，并且与慢性疼痛的发展有关。目前尚不清楚非哺乳动物是否也有这种抑制途径。然而，之前的研究表明，果蝇产生一种名为 Drosulfakinin 的分子，这种分子与哺乳动物在控制疼痛的自上而下信号通路中使用的化学物质相似。为了确定 Drosulfakinin 在控制苍蝇伤害感受中的作用，Oikawa 等人。操纵果蝇神经系统中特定神经元的活性以及相关基因的活性。如果没有果蝇幼虫，果蝇幼虫对热暴露更加敏感，这表明需要该分子来抑制伤害感受。进一步的实验表明，果蝇幼虫的大脑中存在果磺磺胺素，其信号传导的激活会降低昆虫相当于脊髓中传递伤害性信号的神经元的活性。这证实昆虫大脑可以使用与哺乳动物类似的分子，通过自上而下的途径抑制伤害感受。这些发现为使用非哺乳动物进行疼痛研究提供了重要基础。使用遗传技术操纵果蝇伤害感受的能力为理解控制疼痛的自上而下的过程提供了一个强大的工具。这一结果还提出了一种可能性，即这种共享的自上而下的抑制机制可能在 5.5 亿年前就已形成，这可能会导致对伤害感受和疼痛调节系统如何进化的进一步研究。
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 Ca2+ 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. Avoiding harm is fundamental for the survival of animals. Nerve cells called nociceptors can detect potential damage, such as extreme temperatures, sharp objects and certain chemicals. In humans, this detection – known as nociception – leads to signals travelling from nociceptors through the spinal cord to the brain, which perceives them as pain. Mammals such as humans and rodents can inhibit nociception by sending signals from the brain to the spinal cord to dampen pain. This top-down dampening process is believed to play a crucial role in regulating pain in mammals, and it has been implicated in the development of chronic pain. It was not known whether non-mammalian animals shared this inhibitory pathway. However, previous work had shown that fruit fly produce a molecule called Drosulfakinin, which is similar to the chemical that mammals use in the top-down signalling pathway which controls pain. To determine the role of Drosulfakinin in controlling fly nociception, Oikawa et al. manipulated its activity – and the activity of related genes – in specific neurons in the fruit fly nervous system. Without Drosulfakinin, fly larvae were more sensitive to heat exposure, suggesting that this molecule is required to inhibit nociception. Further experiments showed that Drosulfakinin is present only in the brain of fly larvae and activation of its signaling lowers the activity of neurons that transmit nociceptive signals in the insect equivalent of the spinal cord. This confirms that insect brains can dampen nociception via a top-down pathway, using a similar molecule to mammals. The findings provide an important foundation for pain studies using non-mammalian animals. The ability to manipulate nociception using genetic techniques in flies offers a powerful tool to understand the top-down process of controlling pain. This result also raises the possibility that this shared top-down inhibition mechanism may have developed over 550 million years ago, which could lead to further research into how nociception and pain regulation systems evolved.
影响因子：
1.9
作者：
Aldrich BT;Kasuya J;Faron M;Ishimoto H;Kitamoto T
通讯作者：
Kitamoto T