Summary of the mechanisms that may support pain sensitization after surgery leading to persistent postsurgical pain. Nociceptive inputs due to surgery produce local molecular changes such as nerve growth factor (NGF) and cytokine release and in primary sensory neurons of the dorsal root ganglia (DRG) including increased expression of acid-sensing ion channels 3 (ASICS3), transient receptor potential cation channel subfamily V member 1 (TRPV1), and mechanistic target of rapamycin (mTOR). The latter controls vesicular glutamate transporter 2 (VGLUT2) expression that generates an increased glutamatergic activity in the spinal cord. These changes are responsible for peripheral pain sensitization that then influences spinal neuronal activity referred to as central pain sensitization. Central sensitization depends upon increased expression of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and brain-derived neurotrophic factor (BDNF) release. Activation of AMPAR may account for extracellular signal–regulated kinase 1/2 activation (P-ERK1/2) leading to the development of sustained pain hypersensitivity. MAPK kinase p38 activation (P-p38) and chemokine ligand 2 (CCL2) also contribute to surgery-induced central pain sensitization. TrkA = tropomyosin receptor kinase A.