(A) In the classical model of acute pain, painful stimuli are transmitted from the periphery to the dorsal horn via primary afferent fibers (α-δ and C nerve fibers) and from the dorsal horn to the brain via the spinothalamic tract. Pain perception is modulated through the activation of descending inhibitory pathways and the release of neurotransmitters such as norepinephrine, serotonin, and opiate-like substances (endorphins). (B) In the dorsal horn, incoming afferent pain signals cause the release of substance P and excitatory amino acids (EAAs), which bind to activate postsynaptic receptors on the pain transmission neurons (PTNs). Glia are present but quiescent. (C) With intense or prolonged exposure to painful stimuli, incoming afferent signals are increased, and presynaptic release of substance P and EAAs is enhanced. An influx of Ca²⁺ increases the production of nitric oxide, which diffuses out of the PTN and causes the PTN to become hyperexcitable and further enhances the presynaptic release of EAAs and substance P. Glia cells become activated and release substances (e.g., nitric oxide, reactive oxygen species, prostaglandins, proinflammatory cytokines, nerve growth factor) that further increase presynaptic release and postsynaptic hyperexcitability. PTN = pain transmission neuron; EAA = excitatory amino acid; 5-HT = serotonin; NE = norepinephrine; NMDA = N-methyl-D-aspartic acid; AMPA = alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NK-1 = neurokinin; cNOS = constitutive nitric oxide synthase; NO = nitric oxide. (Adapted with permission from Trends Neurosci9 and from Can J Anaesth10 with kind permission from Springer Science and Business Media.)