Preprint
The Primary Cilium and its Hedgehog Signaling in Nociceptors Contribute to Inflammatory and Neuropathic Pain
Research square
02/26/2024
DOI: 10.21203/rs.3.rs-3812442/v1
PMID: 38464172
Abstract
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.
Details
- Title: Subtitle
- The Primary Cilium and its Hedgehog Signaling in Nociceptors Contribute to Inflammatory and Neuropathic Pain
- Creators
- Lindsey A Fitzsimons - Philadelphia College of Osteopathic MedicineLarissa Staurengo-Ferrari - University of California, San FranciscoOliver Bogen - University of California, San FranciscoDioneia Araldi - University of California, San FranciscoIvan J M Bonet - University of California, San FranciscoEthan E Jordan - University of New EnglandJon D Levine - University of California, San FranciscoKerry L Tucker - Philadelphia College of Osteopathic Medicine
- Resource Type
- Preprint
- Publication Details
- Research square
- DOI
- 10.21203/rs.3.rs-3812442/v1
- PMID
- 38464172
- ISSN
- 2693-5015
- eISSN
- 2693-5015
- Grant note
- R01 CA250017 / NCI NIH HHS R21 NS130249 / NINDS NIH HHS P20 GM103643 / NIGMS NIH HHS R01 AR075334 / NIAMS NIH HHS
- Language
- English
- Date posted
- 02/26/2024
- Academic Unit
- Neuroscience and Pharmacology
- Record Identifier
- 9985178659602771
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