Fig. 9.

Cellular events underpinning central sensitization. A, an example of wind up in a single neuron, which is believed to be a key event for the induction of central sensitization. B, the flow of neuronal changes and their behavioral correlates. C, intracellular mechanisms play a role in the development of central sensitization. Excess Ca²⁺ entry into projection neurons, mainly through the NMDA receptor, results in activation of Ca²⁺-dependent enzymes such as PKA, PKB, PKC, and CamKII, which phosphorylate NMDA and AMPA receptors, both enhancing activity directly by promoting channel opening as well as increasing trafficking and insertion into the postsynaptic membrane. Furthermore, activation of the transcription factor CREB may also be involved, which results in increased gene expression and thus production of receptors. (Other heterosynaptic mechanisms are outside the scope of this review.).