Fitzsimons Lindsey A, Staurengo-Ferrari Larissa, Bogen Oliver, Araldi Dioneia, Bonet Ivan J M, Jordan Ethan E, Levine Jon D, Tucker Kerry L
Dept. of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, ME, United States.
Center for Excellence in the Neurosciences, University of New England, Biddeford, ME, United States.
Res Sq. 2024 Feb 26:rs.3.rs-3812442. doi: 10.21203/rs.3.rs-3812442/v1.
The primary cilium, a 1-3 μm long hair-like structure protruding from the surface of almost all cells in the vertebrate body, is critical for neuronal development and also functions in the adult. As the migratory neural crest settles into dorsal root ganglia (DRG) sensory neurons elaborate a single primary cilium at their soma that is maintained into adult stages. While it is not known if primary cilia are expressed in nociceptors, or their potential function in the mature DRG neuron, recent studies have shown a role for Hedgehog, whose signaling demonstrates a dependence on primary cilia, in nociceptor sensitization. Here we report the expression of primary cilia in rat and mouse nociceptors, where they modulate mechanical nociceptive threshold, and contribute to inflammatory and neuropathic pain. When siRNA targeting , a primary cilium-specific intraflagellar transport (IFT) protein required for ciliary integrity, was administered by intrathecal injection, in the rat, it resulted in loss of mRNA in DRG, and primary cilia in neuronal cell bodies, which was associated with an increase in mechanical nociceptive threshold, and abrogation of hyperalgesia induced by the pronociceptive inflammatory mediator, prostaglandin E, and painful peripheral neuropathy induced by a neurotoxic chemotherapy drug, paclitaxel. To provide further support for the role of the primary cilium in nociceptor function we also administered siRNA for another IFT protein, 52. 52 siRNA results in loss of 52 in DRG and abrogates paclitaxel-induced painful peripheral neuropathy. Attenuation of Hedgehog-induced hyperalgesia by knockdown supports a role for the primary cilium in the hyperalgesia induced by Hedgehog, and attenuation of paclitaxel chemotherapy-induced neuropathy (CIPN) by cyclopamine, which attenuates Hedgehog signaling, suggests a role of Hedgehog in CIPN. Our findings support a role of nociceptor primary cilia in the control of mechanical nociceptive threshold and in inflammatory and neuropathic pain, the latter, at least in part, Hedgehog dependent.
初级纤毛是一种从脊椎动物体内几乎所有细胞表面伸出的1-3微米长的毛发状结构，对神经元发育至关重要，在成体中也发挥功能。当迁移的神经嵴定居到背根神经节（DRG）时，感觉神经元在其胞体上形成一根单一的初级纤毛，并维持到成年阶段。虽然尚不清楚初级纤毛是否在伤害感受器中表达，以及它们在成熟DRG神经元中的潜在功能，但最近的研究表明，刺猬信号通路（Hedgehog）在伤害感受器致敏中发挥作用，其信号传导依赖于初级纤毛。在此，我们报告初级纤毛在大鼠和小鼠伤害感受器中的表达，它们在其中调节机械性伤害感受阈值，并参与炎症性疼痛和神经性疼痛。当通过鞘内注射给予靶向初级纤毛特异性的鞭毛内运输（IFT）蛋白的小干扰RNA（siRNA）时，在大鼠中，它导致DRG中该蛋白的信使核糖核酸（mRNA）丢失，以及神经元胞体中的初级纤毛缺失，这与机械性伤害感受阈值升高以及伤害感受性炎症介质前列腺素E诱导的痛觉过敏和神经毒性化疗药物紫杉醇诱导的疼痛性周围神经病变的消除相关。为了进一步支持初级纤毛在伤害感受器功能中的作用，我们还给予了针对另一种IFT蛋白的siRNA。针对该蛋白的siRNA导致DRG中该蛋白缺失，并消除了紫杉醇诱导的疼痛性周围神经病变。通过敲低该蛋白来减弱刺猬信号通路诱导的痛觉过敏，支持初级纤毛在刺猬信号通路诱导的痛觉过敏中发挥作用，而环杷明（一种减弱刺猬信号通路的物质）减弱紫杉醇化疗诱导的神经病变（CIPN），提示刺猬信号通路在CIPN中发挥作用。我们的研究结果支持伤害感受器初级纤毛在控制机械性伤害感受阈值以及炎症性疼痛和神经性疼痛中发挥作用，后者至少部分依赖于刺猬信号通路。
