The role of the thalamic paraventricular nucleus-prelimbic cortex pathway in diabetes-associated mechanical allodynia and thermal hyperalgesia.

Diabetic peripheral neuropathy (DPN) is a chronic complication resulting from diabetes that leads to pain and sensory abnormalities, significantly impacting the quality of life for affected patients. This study aims to investigate the role of glutamatergic neurons in the paraventricular thalamus (PVT) and the prelimbic cortex (PrL) in diabetes-induced nociceptive hypersensitivity. We established a diabetic mouse model through a single intraperitoneal injection of streptozotocin (STZ) and employed fiber photometry, optogenetics, and chemogenetics to examine the responses of glutamatergic neurons in the PVT and PrL to nociceptive stimuli. The results demonstrated that diabetic mice exhibited significant mechanical allodynia in response to von Frey filament (VFF) stimulation, accompanied by a marked increase in glutamatergic neuronal activity in the PVT. Manipulation of PVT glutamatergic neurons through optogenetics altered mechanical thresholds in the mice, indicating the critical role of the PVT to PrL projection in pain perception. Furthermore, chemogenetic modulation of the activity of glutamatergic neurons in both the PVT and PrL similarly affected nociceptive thresholds, further emphasizing the regulatory role of the PVT-PrL glutamatergic pathway in pain processing. Our findings highlight the significance of the PVT-PrL glutamatergic projection in painful diabetic neuropathy-like phenotypes, emphasizing the critical role of central brain circuits in diabetic neuropathy, which has traditionally been characterized primarily as a peripheral condition.