K2P channels as emerging therapeutic targets for pain: insights from functional studies and transcriptomic analyses

Two-pore domain potassium (K2P) channels are major determinants of neuronal excitability through their ability to generate leak potassium currents that control resting membrane potential and action potential firing. Initially considered as passive background channels, K2P channels are now recognized as polymodal sensors integrating mechanical, thermal, chemical, inflammatory, and metabolic signals. Over the past two decades, accumulating evidence has revealed their essential contribution to nociceptive processing and their potential as therapeutic targets for pain disorders. In this review, we provide an integrated overview of K2P channel function in pain, combining data from anatomical, transcriptomic, electrophysiological, genetic, behavioral, and pharmacological studies. We first summarize recent advances defining K2P channel expression throughout the nociceptive system, from peripheral sensory neurons to spinal and supraspinal circuits. Integration of large-scale single-cell transcriptomic datasets from rodents and humans reveals that most K2P members, beyond the historically studied TREK1 and TRESK channels, are expressed in pain-related pathways with distinct cell-type and species-specific patterns. We then discuss how K2P channel expression and function are altered in pathological conditions, including inflammatory, neuropathic, cancer-associated, chemotherapy-induced, migraine-related pain states. Genetic loss-of-function studies consistently demonstrate that reduced K2P activity increases neuronal excitability and promotes pain hypersensitivity, whereas pharmacological activation of selected K2P channels restore inhibitory control and produce analgesic effects. Rather than supporting the existence of a single universal K2P "pain channel", current evidence suggests that different K2P subtypes contribute to specific sensory modalities, neuronal populations, and pathological contexts. Future therapeutic strategies will therefore require identification of the most relevant K2P targets according to pain mechanisms and benefit/risk profiles. Together with advances in structural biology and drug discovery, these findings position K2P channels as a versatile family of targets for precision analgesia and future multimodal treatments aimed at restoring the balance between excitatory and inhibitory mechanisms in chronic pain.