The primary cilium, a single microtubule-based organelle protruding from the cell surface and critical for neural development, also functions in adult neurons. While some dorsal root ganglion neurons elaborate a primary cilium, whether it is expressed by and functional in nociceptors is unknown. Recent studies have shown the role of Hedgehog, whose canonical signaling is primary cilium dependent, in nociceptor sensitization. We establish the presence of primary cilia in soma of rat nociceptors, where they contribute to mechanical threshold, prostaglandin E₂ (PGE₂)-induced hyperalgesia, and chemotherapy-induced neuropathic pain (CIPN). Intrathecal administration of siRNA targeting Ift88, a primary cilium-specific intraflagellar transport (IFT) protein required for ciliary integrity, resulted in attenuation of Ift88 mRNA and nociceptor primary cilia. Attenuation of primary cilia was associated with an increase in mechanical nociceptive threshold in vivo and decrease in nociceptor excitability in vitro, abrogation of hyperalgesia, and nociceptor sensitization induced by both a prototypical pronociceptive inflammatory mediator PGE₂ and paclitaxel CIPN, in a sex-specific fashion. siRNA targeting Ift52, another IFT protein, and knockdown of NompB, the Drosophila Ift88 ortholog, also abrogated CIPN and reduced baseline mechanosensitivity, respectively, providing independent confirmation for primary cilia control of nociceptor function. Hedgehog-induced hyperalgesia is attenuated by Ift88 siRNA, supporting the role for primary cilia in Hedgehog-induced hyperalgesia. Attenuation of CIPN by cyclopamine (intradermal and intraganglion), which inhibits Hedgehog signaling, supports the role of Hedgehog in CIPN. Our findings support the role of the nociceptor primary cilium in control of mechanical nociceptive threshold and inflammatory and neuropathic pain, the latter Hedgehog-dependent.

初级纤毛是一种从细胞表面突出的基于微管的单个细胞器，对神经发育至关重要，在成体神经元中也起作用。虽然一些背根神经节神经元精心设计了初级纤毛，但它是否由伤害感受器表达并在伤害感受器中发挥作用尚不清楚。最近的研究表明，Hedgehog 的经典信号传导是主要纤毛依赖性的，在伤害感受器致敏中的作用。我们确定了大鼠伤害感受器胞体中存在初级纤毛，它们有助于机械阈值、前列腺素 E₂ （PGE₂） 诱导的痛觉过敏和化疗诱导的神经性疼痛 （CIPN）。鞘内施用靶向 Ift88 的 siRNA，Ift88 是纤毛完整性所需的初级纤毛特异性鞭毛内转运 （IFT） 蛋白，导致 Ift88 mRNA 和伤害感受器初级纤毛减弱。初级纤毛的衰减与体内机械伤害感受阈值的增加和体外伤害感受器兴奋性的降低、痛觉过敏的消除以及由原型伤害感受性炎症介质 PGE₂ 和紫杉醇 CIPN 诱导的伤害感受器致敏有关，以性别特异性方式。靶向另一种 IFT 蛋白 Ift52 的 siRNA 和果蝇 Ift88 直系同源物 NompB 的敲低也分别消除了 CIPN 和降低了基线机械敏感性，为伤害感受器功能的初级纤毛控制提供了独立确认。Ift88 siRNA 减弱 Hedgehog 诱导的痛觉过敏，支持初级纤毛在 Hedgehog 诱导的痛觉过敏中的作用。 环巴胺 （皮内和神经节内） 对 CIPN 的减弱抑制 Hedgehog 信号传导，支持 Hedgehog 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症和神经性疼痛中的作用，后者依赖于刺猬。