PACAP attenuates diabetic neuropathic pain by modulating ERK-PGC1α- associated mitochondrial homeostasis

Diabetic neuropathic pain is a debilitating complication of diabetes for which disease-modifying therapies remain limited. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been implicated in neuroprotection and metabolic regulation, but its role in diabetic neuropathic pain remains unclear. Here, we found that patients with diabetic neuropathic pain had reduced serum PACAP-38 levels and elevated pro-inflammatory cytokines compared with patients with diabetes mellitus alone. In streptozotocin-induced diabetic neuropathic pain (DNP) mice, PACAP partially improved body weight recovery but did not markedly reduce fasting hyperglycemia, glucose tolerance or pancreatic islet injury. Importantly, PACAP improved gait performance, attenuated mechanical, thermal, and cold hypersensitivity, and preserved intraepidermal nerve fibers. Transcriptomic and validation analyses showed that diabetic neuropathic pain was associated with endothelial impairment, hypoxia-related signaling, mitochondrial alterations, and redox imbalance in dorsal root ganglia. PACAP treatment partially modulated DNP-related transcriptional changes, including those linked to mitochondrial metabolism, oxidative stress-related processes, and neuronal function. Mechanistically, PACAP increased ERK phosphorylation and PGC1α expression, enhanced mitochondrial biogenesis-related responses, preserved mitochondrial ultrastructure, and improved mitochondrial membrane potential. ERK inhibition with U0126 attenuated PACAP-mediated mitochondrial protection and analgesic effects. These findings suggest that PACAP alleviates DNP through an ERK-PGC1α-associated mechanism that contributes to the restoration of mitochondrial homeostasis in sensory neurons, rather than by substantially correcting systemic hyperglycemia.