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Establishing a Mouse Model of a Pure Small Fiber Neuropathy with the Ultrapotent Agonist of Transient Receptor Potential Vanilloid Type 1
Published on: February 13, 2018
Local keratinocyte-nociceptor interactions enhance obesity-mediated painful small fiber neuropathy via NGF-TrkA-PI3K
Yuta Koui1, Shuxuan Song1,2, Xinzhong Dong3,4
1Laboratory of Stem Cell and Neuro-Vascular Biology, Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
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.
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