Fig. 2

Central sensitization. A Inhibitory and excitatory synapses. Persistent pain or inflammation causes activation and repetitive firing, which triggers release of the excitatory neurotransmitter glutamate in synapses of the dorsal horn. NMDA receptor activity causes Ca²⁺ influx which subsequently can activate intracellular signaling pathways that initiate and maintain central sensitization. In addition, TNF-α, IL-1β, IFNγ and CCL2 release activates NMDA receptors, which contribute to persistent depolarization of the cell membrane. Inhibition is performed by glycinergic and GABAergic synapses. B Glycinergic disinhibition: disinhibition is caused by PGE2 release inducing PKA activity and subsequent phosphorylation of GlyR α3, phosphorylation caused by neuronal PKCγ activity also reduces GlyR currents in PKC γ neurons, loss of GlyR activity due to IL-1β release. Glycine and GABA transporter activity reduces glycine and GABA concentrations in the synaptic cleft, thereby reducing total activity. Release of BDNF inhibits KCC2 cotransporter activity, altering intracellular Cl^– concentrations and increasing glycinergic disinhibition