Molecular and neural mechanisms underlying physiological and pathological cold sensation

Cold sensation is gaining clinical significance in the diagnosis, prognosis, and treatment of chronic pain. Despite this, mechanisms responsible for normal and abnormal cool/cold detection remain underexplored compared to other sensory modalities. This narrative review presents a synthesis of innocuous cool and noxious cold processing in a standard stepwise framework spanning five stages of transduction, transmission, spinal modulation, projection, and ascending/descending cortical activity. Synthesizing molecular, anatomical, functional, and behavioral evidence, this review suggests that cold sensation relies on highly specialized, though still emerging, molecular and circuit-level frameworks. Specifically, we propose the possibility of P2Y1 role in noxious cold signaling and re-evaluate the potential mechanistic contribution of Nav1.3 to neuropathic cold hypersensitivity. The narrative translates these molecular findings for potential clinical application, advancing the case for cold-specific quantitative sensory testing (QST) as a vital biomarker for assessing descending pain modulation and chronic pain phenotypes.