Targeting Spinal Dorsal Horn Sensitisation in Chronic Pain: Mechanisms and Translational Strategies

Abstract Chronic pain is a multidimensional, highly debilitating disease arising from diverse functional and structural impairments across the nervous system. Despite heterogeneous aetiologies, chronic pain states converge on shared pathophysiological mechanisms: peripheral and central sensitisation. These dysfunctions reflect long-term functional and structural plasticity within the peripheral and central nociceptive pathways, resulting in amplified signal transmission and pain chronification. Historically, research and drug development prioritised peripheral targets to suppress nociceptive inputs, often neglecting central sensitisation, a core mechanism of treatment-resistant pain. Sensitisation of dorsal horn (DH) circuits underlies network hyperexcitability associated with disrupted excitation-inhibition balance, synaptic potentiation, and circuit reorganisation. This review summarises recent advances in delineating synaptic, cellular, and DH network-level adaptations underlying chronic pain. We discuss emerging mechanism-based strategies to restore circuit balance by targeting cell-type-specific maladaptive plasticity rather than globally suppressing neural activity. Targeted approaches hold promise for improving the specificity, efficacy, and safety of next-generation chronic pain therapies.