Key intracellular pathways contributing to the generation of central sensitization. NMDAR activation causes activation of PKC, CaMKII, and ERK (black arrows); GluR1-containing AMPAR activate PKC (red arrow); NK1 and CGRP1 receptors activate PKC, PKA, and ERK (orange and brown arrows, respectively); TrkB s activates of PKC and ERK (purple arrows); and mGluR, via release of Ca2+ from microsomal stores, activates PKC and ERK (gray arrows). Note that most of the triggers of central sensitization: Activation of NMDAR, mGluR, TrkB, NK1, CGRP1, or B2 converge to activate ERK.