Role of Nociceptor Primary Cilia in Inflammatory and Neuropathic Pain

This project earned a two-year R21 grant from the National Institutes of Health to investigate a novel cellular mechanism in pain control. The project focuses on primary cilia—short, hair-like projections present on nearly all cells—and their role in neurons that detect and transmit painful stimuli. Although primary cilia are known to be critical for neuronal development and function, their specific role in nociceptors, the sensory neurons responsible for signaling pain, is not understood.

The researchers propose that these structures may act as specialized signaling hubs that process pain-inducing cues, with implications for both inflammatory and neuropathic pain. The work is motivated by the substantial clinical and societal burden of chronic pain in the United States, where more than 50 million adults report persistent pain and the associated loss of work is estimated at over $80 billion annually. Existing pain treatments, including opioid therapy, carry significant adverse effects and costs, underscoring the need for new mechanistic insights that could lead to safer and more effective interventions. Theproject addresses this need by exploring an understudied cellular structure and a signaling pathway that may be amenable to pharmacological modulation. A central focus of the research is the Hedgehog signaling pathway, an evolutionarily conserved system that informs cell differentiation and development. Recent studies in model organisms including fruit flies and rats have implicated Hedgehog signaling in the development and maintenance of pain responses. Importantly, in mammals the Hedgehog pathway operates in a manner that depends on intact primary cilia, linking the cellular structure and the signaling cascade in a coherent mechanistic hypothesis. This R21-funded research will test whether primary cilia on pain neurons are essential for transducing or modulating nociceptive signals via Hedgehog or related pathways.

The translational significance of this line of inquiry is heightened by the existence of clinically approved Hedgehog-pathway inhibitors used in oncology. If primary cilia-mediated Hedgehog signaling contributes to pathological pain, there may be potential to repurpose or adapt existing compounds for pain modulation, accelerating translation compared with de novo drug discovery. The project thus combines fundamental cell- and neuron-level investigation with an eye toward therapeutic relevance. By elucidating the role of primary cilia in nociceptor function and their relationship to Hedgehog signaling, Tucker’s research aims to reveal new pathways and targets for treating chronic pain. The R21 grant supports exploratory, high-impact research designed to clarify whether primary cilia are functional mediators of pain signaling and whether interfering with cilia-dependent pathways can alter pain outcomes.

The findings could open new directions for basic neurobiology and inform future clinical strategies to reduce the burden of chronic pain while limiting reliance on therapies with substantial side effects.