Central signaling pathways contribute to chronic pain. In the ACC, glutamate is the major fast excitatory transmitter between input fibers and pyramidal cells. Peripheral injury such as tissue inflammation or nerve injury trigger a burst of abnormal activity in the ACC circuits; and subsequently activate postsynaptic NMDA receptors on cingulate pyramidal cells located in layer II-III. Activation of NMDA receptor triggers calcium influx. In adult ACC pyramidal cells, most of NMDA receptors are the combination of NR1-NR2A, NR1-NR2B with possible minor component of currents made of NR1-NR2A-NR2B. Postsynaptic increases in Ca2+ leads to activation of Ca2+-calmodulin (CaM) dependent pathways. Among them, Ca2+ and CaM stimulated AC1 is activated, and this activation leads to the generation of the key second messenger cAMP. Subsequently, cAMP activates PKA. PKA then translocates to the nucleus and phosphorylates CREB. NR2B contains a CREB binding domain which may couple increases in intracellular calcium with the increase in NR2B expression. Subsequently, postsynaptic synthesis of NMDA NR2B is increased, and together with endogenous motor protein KIF17, these new NR2B subunits are added to postsynaptic NMDA receptors. Such positive feedback control may further enhance neuronal excitability within the ACC, and contribute to chronic pain.