Cold sensation and pathological cold pain in mammals: analysis of the underlying molecular mechanisms and therapeutic strategies

Mammals rely on the cold sensation pathway to detect environmental thermal fluctuations and respond appropriately, which is critical to their survival. Specifically, Aδ and C fibres convey temperature information to the dorsal horn of the spinal cord (DH); after integration, this information is transmitted to the thalamus or hypothalamus, and then to higher-level centers to enable the perception of cold or the regulation of body temperature. In this process, cold sensation conduction-related ion channels such as transient receptor potential (TRP) channels and voltage-gated ion channels can convert temperature information into electrical signals and regulate neuronal excitability, respectively, thereby affecting the transmission of cold sensation. However, in certain conditions that cause neuropathic pain, such as chemotherapy-induced peripheral neuropathy (CIPN), diabetic peripheral neuropathy (DPN) and central poststroke pain (CPSP), the body experiences pathological cold pain, which severely affects the quality of life of patients. The development of pathological cold pain is closely related to disruptions in cold sensation pathways, including neuronal sensitization, ion channel abnormalities, aberrant immune-inflammatory responses. There are currently some treatment strategies for pathological cold pain, but most focus on neuropathic pain, and treatment approaches specifically targeted at pathological cold pain remain scarce. This narrative review comprehensively elaborates on the molecular mechanisms of cold transmission and pathological cold pain, and summarizes current treatment options, thereby providing new insights into the identification of therapeutic targets and clinical translation in the treatment of pathological cold pain.