Hippocampal remodeling in chronic pain: Structural, functional, cellular, metabolic, and molecular mechanisms and therapeutic perspectives.

Chronic pain is a multifaceted condition characterized by persistent nociceptive signaling and maladaptive central nervous system plasticity, in which the hippocampus has emerged as a critical hub of structural, functional, metabolic, and molecular remodeling. This review systematically synthesizes current evidence on hippocampal alterations in chronic pain across multiple levels, including structural remodeling (e.g., gray matter atrophy and impaired neurogenesis), functional and circuit-level disruptions, metabolic dysregulation, and cellular and molecular mechanisms. In particular, we highlight convergent pathways involving neurotransmitter and receptor dysregulation, cytokine-driven neuroinflammation, neurotrophic signaling deficits, and additional molecular alterations that collectively impair synaptic plasticity and hippocampal network stability. Importantly, we propose a multiscale integrative framework in which synaptic imbalance, neuroimmune activation, and neurotrophic dysregulation interact to drive hippocampal dysfunction, forming a bidirectional loop that links pain, emotion, and cognition. We further discuss therapeutic strategies targeting hippocampal remodeling, including pharmacological, metabolic, neuroimmune, and circuit-level neuromodulation approaches, as well as emerging precision medicine strategies. By integrating preclinical and clinical evidence, this review positions the hippocampus as a central node in chronic pain pathophysiology and a promising target for developing interventions that address both nociceptive and comorbid affective and cognitive symptoms. These insights support a unified model of hippocampal remodeling in chronic pain that may guide future precision diagnostics and targeted interventions.