Local keratinocyte-nociceptor interactions enhance obesity-mediated painful small fiber neuropathy via NGF-TrkA-PI3K signaling axis.

The pathology of painful small fiber neuropathy, characterized by neuropathic pain and axon degeneration, develops locally within the skin during the stages of obesity and pre-diabetes. However, the initiation and progression of morphological and functional abnormalities in skin sensory nerves remains elusive. We evaluated pain-associated wiping behavior and conducted ex vivo live Ca2+ imaging of the diet-induced obesity (DIO) ear skin to detect sensory hypersensitivity. Our findings reveal sensory hypersensitivity in skin nociceptive axons followed by axon degeneration. Further mechanistic analysis identified keratinocytes as a major source of nerve growth factor (NGF) in DIO skin, which locally sensitizes nociceptors through NGF and its receptor tropomyosin receptor kinase A (TrkA)-mediated downstream signaling, including the phosphoinositide-3-kinases (PI3K) pathway. Thus, targeting these local interactions between keratinocytes and nociceptors offers a therapeutic strategy for managing neuropathic pain, avoiding the adverse effects associated with systemic interventions.