Figure 1: Postsynaptic NMDA-NOS-NO pathway enhances presynaptic glutamate release and postsynaptic transmission, and activates glia in persistent pain. In acute pain, glutamate, SP, and ATP are released from the presynaptic neuron. Glutamate activates AMPA receptor and induces generator potential, which opens NaV causing action potential. Once the acute noxious stimuli and inflammatory response has gone, the pain would disappear. When repetitive noxious stimulation continues, SP activates NK-1 receptor, causing PLC activation making IP3 and DAG from phospholipid. IP3 stimulates Ca2+ release from Ca2+ stored site. Increased Ca2+ and DAG activates C kinase which phosholylates NMDA receptor with subsequent Ca2+ and Na+ influx into the postsynaptic secondary neuron, followed by activation of nNOS, NO production, Guanylyl cyclase activation, cGMP formation, activation of GK, inducing the further activation of NMDA receptor. NO produced in the secondary neuron diffuses out of the neuron and reach the presynaptic neuron and neighboring glial cell. In the presynaptic neuron NO-induced GK activation closes K channel with its phosphorylation and opens HNC, causing depolarization with subsequent activation of Ca2+ channel. Increase in Ca2+ releases the glutamate and SP into the synaptic cleft causing vicious cycle. AMPA,α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ATP, adenosine triphosphate; CaV, voltage-activated calcium channel; cGMP, cyclic guanosine- 3’,5’monophosphate; CaMK II, calcium calmodulin kinase II; DAG, diacylglycerol; EP, prostaglandin E receptor; GC, guanylyl cyclase; GK, cGMP dependent protein kinase; Glu, glutamate; SP, substance P; HNC, hyperpolarization-activated cyclic nucleotide-gated channels ; IP3, inositol triphosphate; NK-1, neurokinin-1 receptor; NaV, voltage-activated sodium channel; NMDA, N-methyl-D-aspartate; nNOS, neuronal nitric oxide synthase: NO, nitric oxide; PGE, prostaglandin E; PKC, protein kinase C; PLC, phosopholipase C; S-nitro, S-nitrosylation; SKF, Src-family kinase;