Figure 5.

Sources of Ca²⁺ in the synapse of nociceptive neurons for inducing central sensitization. (A), Model of a nociceptor–dorsal horn neuron synapse under control, nonactivated conditions. After nociceptor input (B), activation of NMDAR and mGluR result in a rapid increase of [Ca²⁺]i that activates PKC and CaMKII, 2 major effectors of central sensitization. (C), Representation of a synapse during peripheral inflammation-induced central sensitization, where there is a shift from GluR2/3 to GluR1-containing AMPARs that enables, along with voltage-dependent calcium channels and NMDAR, entry of Ca²⁺ and which, together with activation of the G-coupled MGluR, NK1, B2, and CGRP1 receptors, which release intracellular Ca²⁺ stores, recruits PKC and CaMKII, strengthening the excitatory synapse.