初级纤毛,从脊椎动物体内几乎所有细胞的表面突出的1-3μm长的毛发状结构,对神经元发育至关重要,在成人中也起作用。当迁移的神经c沉积到背根神经节(DRG)时,感觉神经元在其躯体上形成单个初级纤毛,并保持到成年阶段。虽然不知道初级纤毛是否在伤害感受器中表达,或者它们在成熟DRG神经元中的潜在功能,最近的研究表明刺猬的作用,其信号显示出对初级纤毛的依赖,在伤害性感受器致敏中。在这里,我们报告了大鼠和小鼠伤害感受器中初级纤毛的表达,它们调节机械伤害感受阈值,并导致炎症和神经性疼痛。当siRNA靶向Ift88时,纤毛完整性所需的初级纤毛特异性鞭毛内转运(IFT)蛋白,通过鞘内注射给药,在老鼠身上,它导致DRG中Ift88mRNA的丢失,神经元细胞体中的初级纤毛,这与机械伤害感受阈值的增加有关,和消除由前疼痛感觉炎症介质诱导的痛觉过敏,前列腺素E2和神经毒性化疗药物引起的疼痛性周围神经病变,紫杉醇。为了进一步支持初级纤毛在伤害感受器功能中的作用,我们还对另一种IFT蛋白施用siRNA,Ift52.Ift52siRNA导致DRG中Ift52的丢失并废除紫杉醇诱导的疼痛性周围神经病变。通过Ift88敲低减轻Hedgehog诱导的痛觉过敏支持原发性纤毛在Hedgehog诱导的痛觉过敏中的作用,和环巴胺减轻紫杉醇化疗诱导的神经病变(CIPN),削弱刺猬信号,表明刺猬在CIPN中的作用。我们的研究结果支持伤害感受器初级纤毛在控制机械伤害感受阈值以及炎性和神经性疼痛中的作用。后者,至少在某种程度上,依赖刺猬。
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 Ift88, 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 Ift88 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 E2, 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, Ift52. Ift52 siRNA results in loss of Ift52 in DRG and abrogates paclitaxel-induced painful peripheral neuropathy. Attenuation of Hedgehog-induced hyperalgesia by Ift88 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.