Thermal vulnerability in migraine: thermosensory pathways, central sensitization and neuropeptide release

Diurnal and seasonal ambient temperature fluctuations are well-documented environmental precipitants of migraine attacks, particularly in patient subgroups with prominent temperature hypersensitivity. This narrative review systematically integrates human thermoregulatory neural circuits, nociceptive ion channel signaling, neuropeptide/serotonergic modulation, and cortical excitatory changes to delineate multi-layered mechanisms underlying temperature-triggered migraine. Cutaneous thermosensitive transient receptor potential channels, particularly cold-sensing transient receptor potential melastatin 8 (TRPM8), transduce thermal signals to the spinal dorsal horn and lateral parabrachial nucleus (LPB). The LPB-central amygdala (CeA) calcitonin gene-related peptide (CGRP) pathway acts as a critical thermo-nociceptive hub, driving central sensitization upon cold stimulation. CGRP exerts context-dependent effects on thermoregulation: it facilitates heat dissipation via cutaneous vasodilation, contributes to cold-induced thermogenesis through hypothalamic, autonomic, and brown adipose tissue (BAT) pathways, and concurrently amplifies nociceptive signaling in the trigeminovascular system. However, the degree to which these thermoregulatory actions influence susceptibility to temperature-related migraine remains unresolved. Serotonin (5-HT) and pituitary adenylate cyclase-activating polypeptide (PACAP) serve as dual-effect mediators that coordinate physiological thermoregulation and migraine-related neuroinflammation, mast cell degranulation, and meningeal vasodilation. Hyperthermia additionally lowers the initiation threshold of cortical spreading depression (CSD), the electrophysiological correlate of migraine aura, through disrupted ionic homeostasis and enhanced glutamatergic release. Cumulative evidence demonstrates that thermal stress converges on shared molecular and neural pathways governing thermoregulation and pain sensitization, rendering temperature-sensitive individuals with migraine uniquely vulnerable to headache onset and chronification. Targeting TRPM8, CGRP, PACAP, or 5-HT 7 receptors may offer therapeutic strategies for this susceptible patient population.