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bioRxiv · 10.1101/2025.10.27.684945

Keratinocyte Pannexin-1 is essential for Mechanical Hypersensitivity following Traumatic Peripheral Nerve Injury

Stucky, C. L.·Mecca, C. M.·Isaeva, O. L.·Mikesell, A. R. M. R.·Sriram, A. L.·Stuart, B. A.·Dharanikota, B. L.
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Abstract

Neuropathic pain remains one of the most prevalent and challenging forms of chronic pain to manage. It is characterized by severe cutaneous touch and cold evoked pain. Whereas the contribution of peripheral nerves to neuropathic pain is well established, the influence of peripheral non-neuronal cells that interact with injured nerves has not been studied in depth. Keratinocytes, the primary cell type in the epidermis, play an important role in the initial processing of environmental mechanical and thermal stimuli under normal conditions. Here, we investigated the role of keratinocytes following traumatic peripheral nerve injury and determined that these cells contribute to injury-associated heightened sensation. We performed tibial spared nerve injury (tSNI) in mice that selectively express archaerhodopsin in keratinocytes to temporally reduce activity from these cells at various timepoints following injury. Brief (5 min) optogenetic inhibition completely reversed both the mechanical and cold hypersensitivity at acute (4 days) and throughout chronic (17 weeks) timepoints following tSNI. Keratinocytes isolated from the spared glabrous skin dermatome were sensitized to mechanical and cold stimuli and found to release factors that enhance activity of sensory neurons. Moreover, we found that keratinocyte phospholipase A2 (PLA2) driven activation of pannexin-1 is critical for the long term development of mechanical allodynia. This discovery indicates that keratinocytes contribute substantially to the mechanical and cold allodynia after traumatic nerve injury and suggest that keratinocytes may be a topical therapeutic target to alleviate the severe touch- and cold-evoked cutaneous pain following peripheral nerve injury.

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Stucky, C. L., Mecca, C. M., Isaeva, O. L., Mikesell, A. R. M. R., Sriram, A. L., Stuart, B. A., Dharanikota, B. L.. 2025-10-28. Keratinocyte Pannexin-1 is essential for Mechanical Hypersensitivity following Traumatic Peripheral Nerve Injury. https://doi.org/10.1101/2025.10.27.684945

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