From peripheral neurotoxicity to central dysfunction: linking neuropathic pain and cognition in chemotherapy-induced...

Chemotherapy-induced peripheral neurotoxicity (CIPN) represents a significant clinical burden, affecting 70-80 % of patients during treatment and persisting chronically in 20-30 % of survivors. While peripheral nerve injury is the primary pathological hallmark, emerging evidence demonstrates that central nervous system (CNS) dysregulation plays a crucial role in pain chronification and associated cognitive impairment. This review synthesizes recent findings on cortical and subcortical alterations that drive neuropathic pain processing in CIPN, examining dysregulated glutamatergic and GABAergic neurotransmission, altered voltage-gated ion channel expression, and central sensitization across key pain-modulatory brain regions including the prefrontal cortex, anterior cingulate cortex, somatosensory cortices, and periaqueductal gray. We address chemotherapy-induced cognitive impairment ("chemobrain") as a manifestation of shared neuroinflammatory mechanisms linking peripheral nerve injury to CNS pathology. In fact, peripheral neuropathy-triggered neuroinflammation, characterized by microglial activation and cytokine dysregulation, compromises the blood-brain barrier and impairs hippocampal-dependent memory, synaptic plasticity, and adult neurogenesis. The paper integrates findings from both animal models and human patients and discusses how animal models of CIPN reveal central nervous system engagement beyond peripheral pathology. This review emphasizes CIPN as a disorder profoundly affecting central pain modulation and cognition, requiring integrated therapeutic strategies addressing both peripheral and central nervous system pathology.