Growth Factor Signaling Regulates Mechanical Nociception in Flies and Vertebrates
Growth Factor Signaling Regulates Mechanical Nociception in Flies and Vertebrates
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DOI：
10.1523/jneurosci.2950-18.2019
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发表时间：
2019-07-24
影响因子：
5.3
通讯作者：
Gutstein, Howard B.
中科院分区：
文献类型：
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作者：
Lopez-Bellido, Roger;Puig, Stephanie;Gutstein, Howard B.
机械敏化是临床上最难治疗的疼痛问题之一。然而，机械性伤害性感受的分子和遗传学基础尚不清楚。在这里，我们开发了一个果蝇机械性伤害性感受模型，以研究调节机械性伤害性感受的离子通道和信号通路。我们制作的von Frey纤维可以跨越果蝇幼虫的亚阈值到高毒害范围。利用这些，我们发现压力(力/面积)，而不是力本身，是对有害机械刺激的厌恶滚动反应的主要决定因素。我们证明了RTK、PDGF/VEGF受体(PVR)及其配体(PVF2和3)是机械伤害性感受和正常树突状分支所必需的。PVR在IV类感觉神经元中表达并发挥功能，而Pvf2和Pvf3则由多个组织产生。PVR及其配体的结构性过表达或PVR的诱导性过表达导致了机械超敏反应，这种反应可以部分地与形态效应分离。遗传分析表明，Piezo和Pain离子通道是PVR信号异位激活时观察到的机械过敏所必需的。PDGF，而不是血管内皮生长因子，可引起大鼠机械超敏反应。药物抑制血管内皮生长因子受体2型(VEGFR-2)信号可减轻大鼠的机械性伤害性感受，提示PDGF和VEGFR-2信号在机械性伤害性感受调节中具有保守的作用。VEGFR-2的抑制也降低了大鼠对吗啡的镇痛耐受性。我们的结果表明，保守的RTK信号通路调节苍蝇和大鼠的基线机械伤害性感受。
Mechanical sensitization is one of the most difficult clinical pain problems to treat. However, the molecular and genetic bases of mechanical nociception are unclear. Here we develop a Drosophila model of mechanical nociception to investigate the ion channels and signaling pathways that regulate mechanical nociception. We fabricated von Frey filaments that span the subthreshold to high noxious range for Drosophila larvae. Using these, we discovered that pressure (force/area), rather than force per se, is the main determinant of aversive rolling responses to noxious mechanical stimuli. We demonstrated that the RTK PDGF/VEGF receptor (Pvr) and its ligands (Pvfs 2 and 3) are required for mechanical nociception and normal dendritic branching. Pvr is expressed and functions in class IV sensory neurons, whereas Pvf2 and Pvf3 are produced by multiple tissues. Constitutive overexpression of Pvr and its ligands or inducible overexpression of Pvr led to mechanical hypersensitivity that could be partially separated from morphological effects. Genetic analyses revealed that the Piezo and Pain ion channels are required for mechanical hypersensitivity observed upon ectopic activation of Pvr signaling. PDGF, but not VEGF, peptides caused mechanical hypersensitivity in rats. Pharmacological inhibition of VEGF receptor Type 2 (VEGFR-2) signaling attenuated mechanical nociception in rats, suggesting a conserved role for PDGF and VEGFR-2 signaling in regulating mechanical nociception. VEGFR-2 inhibition also attenuated morphine analgesic tolerance in rats. Our results reveal that a conserved RTK signaling pathway regulates baseline mechanical nociception in flies and rats.