Keratinocyte-nociceptor interactions via NGF-TrkA-PI3K signaling axis promote pain behaviors and sensory hypersensitivity in diabetic small fiber neuropathy

Authors

• Y Koui
• S Song
• Y Mukoyama

Abstract

The pathology of small fiber neuropathy, characterized by neuropathic pain and axon degeneration, develops locally within the peripheral skin in obese or pre-diabetic patients. However, the mechanism underlying the initiation and progression of morphological and functional abnormalities in skin nociceptive nerves remains elusive. We utilized diet-induced obesity (DIO) mouse ear skin not only to evaluate pain-associated wiping behavior but also to measure painful sensory hypersensitivity, characterized by abnormal high excitation of nociceptive axons, using ex vivo live calcium imaging. Our time-course analysis revealed that DIO enhances neuropathic pain behaviors and sensory hypersensitivity simultaneously. Moreover, we found neuropathic pain behaviors and sensory hypersensitivity followed by axon degeneration. Further mechanistic analysis identified that skin epidermal keratinocytes express nerve growth factor (NGF) in DIO skin, which locally sensitizes nociceptive axons through NGF-Tropomyosin receptor kinase A (TrkA)-phosphatidylinositol 3-kinase (PI3K) signaling. The local inhibition of NGF-TrkA-PI3K signaling by an anti-NGF neutralized antibody or a selective inhibitor of PI3K suppresses sensory hypersensitivity in DIO skin, which suggests that targeting local keratinocyte-nociceptor interactions via NGF-TrkA-PI3K signaling offers a therapeutic strategy for diabetic small fiber neuropathy. We also observed increased vascular permeability in the dermal capillaries of DIO skin at the same time we noted neuropathic pain behaviors and sensory hypersensitivity. Since insulin enhances NGF expression in keratinocytes, increased vascular permeability may facilitate the diffusion of circulating insulin into the epidermis. Collectively, local inhibition of NGF-TrkA-PI3K signaling axis could be an effective therapeutic strategy for diabetic small fiber neuropathy, potentially circumventing drug side effects caused by systemic interventions.

Scientific Focus Area: Neuroscience

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