The Primary Cilium and its Hedgehog Signaling in Nociceptors Contribute to Inflammatory and Neuropathic Pain.

Autor: Fitzsimons LA; 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., Staurengo-Ferrari L; Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California San Francisco, San Francisco, United States., Bogen O; Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California San Francisco, San Francisco, United States., Araldi D; Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California San Francisco, San Francisco, United States., Bonet IJM; Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California San Francisco, San Francisco, United States., Jordan EE; 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., Levine JD; Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California San Francisco, San Francisco, United States., Tucker KL; 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.
Jazyk: angličtina
Zdroj: Research square [Res Sq] 2024 Feb 26. Date of Electronic Publication: 2024 Feb 26.
DOI: 10.21203/rs.3.rs-3812442/v1
Abstrakt: 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 E 2 , 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, Ift 52. Ift 52 siRNA results in loss of Ift 52 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.
Competing Interests: Conflict of interest statement The authors declare no competing interests. Additional Declarations: There is NO Competing Interest.
Databáze: MEDLINE
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