Figure 4. Nerve injury leads to the release of glutamate (Glu) from the central terminals of primary nociceptive afferents. Glutamate activates the N-methyl D-aspartate receptor (NMDA-R), which leads to calcium influx and increased production of nitric oxide. An increase in nitric oxide leads to activation of cyclic guanosine monophosphate and various protein kinases (PKs). These substances then act as a feedback mechanism at the NMDA-R (positive feedback) and [micro sign]-opioid receptor (negative feedback). This means that subsequent administration of morphine results in a vicious cycle, with further positive feedback at the NMDA-R. (Reproduced with permission from Siddall and Cousins. [  7 ])