Keratinocytes Contribute to Traumatic Nerve Injury-Induced Mechanical Hypersensitivity

Neuropathic pain is a debilitating health condition that affects nearly 3-17% of the general population and is associated with severe cutaneous mechanical allodynia. Neuropathic pain is one of the most challenging types of chronic pain to manage effectively. Since keratinocytes are the first cell impacted by touch stimuli, we asked whether keratinocytes may be involved in the neuropathic mechanical allodynia. Exploring peripheral keratinocytes in neuropathic pain may reveal new targets for topical treatments, minimizing central nervous system side effects and improving pain treatment efficacy. Our lab and others have demonstrated the crucial role of keratinocytes, a major cell type in the epidermis, in the initial processing of mechanical information under healthy conditions. The goal of this study is to evaluate the role of keratinocytes to touch evoked pain after traumatic nerve injury, where the keratinocytes themselves are not directly damaged. To investigate this, a surgical model of traumatic nerve injury, the tibial spared nerve injury (tSNI), was used. We found that optogenetic inhibition of keratinocytes during behavioral assessment attenuated tSNI-induced mechanical hypersensitivity to innocuous and noxious punctate and dynamic stimuli. Furthermore, extrudate from cultured keratinocytes isolated from tSNI mice induced (1) behavioral mechanical hypersensitivity when injected into naïve mouse paws and (2) increased calcium responses to a low potassium test stimulus (20mM KCl) in naïve sensory neuron cultures during calcium imaging experiments. Together, these findings highlight the role that keratinocytes may play in hypersensitivity following nerve injury. Funding: R01 NS070711 (CLS), R37 NS108278 (CLS).