Journal article
The Nociceptor Primary Cilium Contributes to Mechanical Nociceptive Threshold and Inflammatory and Neuropathic Pain
The Journal of neuroscience, Vol.44(47), p.e1265242024
11/20/2024
DOI: 10.1523/JNEUROSCI.1265-24.2024
PMID: 39349056
Abstract
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 E
(PGE
)-induced hyperalgesia, and chemotherapy-induced neuropathic pain (CIPN). Intrathecal administration of siRNA targeting
, a primary cilium-specific intraflagellar transport (IFT) protein required for ciliary integrity, resulted in attenuation of
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 PGE
and paclitaxel CIPN, in a sex-specific fashion. siRNA targeting
, another IFT protein, and knockdown of NompB, the
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
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.
Details
- Title: Subtitle
- The Nociceptor Primary Cilium Contributes to Mechanical Nociceptive Threshold and Inflammatory and Neuropathic Pain
- Creators
- Lindsey A Fitzsimons - University of New EnglandLarissa Staurengo-Ferrari - University of California, San FranciscoEugen V Khomula - University of California, San FranciscoOliver Bogen - University of California, San FranciscoDionéia Araldi - University of California, San FranciscoIvan J M Bonet - University of California, San FranciscoPaul G Green - University of California, San FranciscoEthan E Jordan - University of New EnglandFinn Sclafani - University of New EnglandConnor E Nowak - University of New EnglandJulie K Moulton - University of New EnglandGeoffrey K Ganter - University of New EnglandJon D Levine - University of California, San FranciscoKerry L Tucker - University of New England
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.44(47), p.e1265242024
- DOI
- 10.1523/JNEUROSCI.1265-24.2024
- PMID
- 39349056
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Grant note
- R01 CA250017 / NCI NIH HHS R21 NS130249 / NINDS NIH HHS P20 GM103643 / NIGMS NIH HHS R01 AR075334 / NIAMS NIH HHS R15 NS131952 / NINDS NIH HHS
- Language
- English
- Date published
- 11/20/2024
- Academic Unit
- Neuroscience and Pharmacology
- Record Identifier
- 9985178664002771
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