Fig. (3). Identifying a cognitive gene in chronic pain.

Peripheral injury such as tissue inflammation or nerve injury leads to a burst of abnormal activity, and subsequently activates postsynaptic NMDAR. This triggers Ca²⁺ influx, leading to activation of Ca²⁺/CaM-dependent pathways, including AC1. AC1 activation leads to the generation of cAMP, which activates PKA. PKA then translocates to the nucleus and phosphorylates CREB. Postsynaptic synthesis of NMDA NR2B is then increased, and the new NR2B subunits are added to postsynaptic NMDAR. This may further enhance neuronal excitability and contribute to chronic pain.