Preservation of Nociceptor Intraepidermal Nerve Fibres in Diabetic Neuropathic Pain

Peripheral painful sensory neuropathy represents a prevalent and disabling complication of Type 1 and Type 2 diabetes. Unfortunately, despite the clinical need for improved analgesic approaches, clinicians remain inadequately provisioned to treat these patients as many analgesics are ineffective or initiate undesirable health-impacting side effects. During diabetes, the viability of the peripheral sensory nervous system is vulnerable, depicted by sensory neurodegeneration and neuropathic pain. However, it remains undefined how nociceptor intraepidermal fibre innervations are affected in patients and rodent models. Here, rodent models of chemically induced Type 1 and dietary induced prediabetes/Type 2 diabetic peripheral sensory neuropathy were utilised to investigate the impact upon nociceptor degeneration in painful diabetic neuropathy. Streptozotocin-induced Type 1 diabetes as well as 42% and 60% high-fat diets caused mechanical allodynia when compared with age-matched controls. Furthermore, dietary interventions led to a sustained hypersensitivity to thermal stimuli and a transient mechanical allodynia that was observed in the early phase, which later resolved. Histological analysis of plantar skin of the hind limbs demonstrated a significant reduction in total intraepidermal nerve fibre (IENF) density (PGP9.5 labelled), indicating sensory neurodegeneration in Type 1 and prediabetes/Type 2 diabetic rodent models. However, CGRP-positive nociceptor IENFs remain preserved, pointing to differential vulnerability among sensory fibre subtypes. Additionally, in Type 1, there was an increased presence of Langerhan cells, whereas this was not presented in the dietary induced models. This provides mechanistic insight into painful diabetic neuropathy and provides fundamental understanding that will support improved treatment of diabetic sensory neuropathy.