Neuropathic Pain: From Mechanisms to Therapeutic Interventions

Neuropathic pain is caused by injury or disease of the somatosensory system. It involves peripheral nerve injury, central sensitization, transmitter imbalance, glial activation, and large-scale network remodeling. Despite substantial advances in pain biology, clinical assessment continues to rely predominantly on patient-reported symptoms, sensory examination, and conventional neurophysiological testing, approaches that often fail to delineate the predominant biological mechanisms underlying pain in individual patients. Recent advances in sensory phenotyping and multimodal imaging have enabled in vivo characterization of abnormalities at the receptor, neuroinflammatory, and circuit levels, thereby providing a foundation for mechanism-based stratification and more individualized therapeutic decision-making. This review summarizes neuropathic pain from clinical stratification to mechanism-based imaging and therapeutic intervention. We describe key clinical dimensions, including sensory gain, sensory loss, peripheral and central pain generators, mixed nociceptive-neuropathic pain, central sensitization, and autonomic or small-fiber modifiers. These dimensions help explain why patients with the same diagnosis may show different symptoms and treatment responses. We also review major molecular mechanisms, including glutamatergic overactivity, GABAergic and glycinergic disinhibition, monoaminergic remodeling, and neuroimmune modulation. These changes reshape spinal, thalamocortical, limbic, salience, reward, cerebellar, and descending control circuits. Peripheral nerve ultrasound and MR neurography can help identify structural peripheral pain generators. PET, MRS, MRI, DTI, fMRI, EEG, and multimodal imaging can assess receptor availability, neurotransmitter balance, neuroinflammation, white matter integrity, and network connectivity. These imaging tools may link clinical phenotypes with biological mechanisms and help define mechanism-based subtypes. Imaging biomarkers may also support treatment selection, treatment monitoring, neuromodulation targeting, and translational trial design. This framework supports a shift from symptom-based assessment to mechanism-guided precision care for neuropathic pain.