Figure 4.

Two distinct models for the role of glutamate (Glu) transporter inhibitors in pathological pain. Pathological pain might cause Glu uptake decrease and energy insufficiency in the spinal cord. The latter may, in turn, results in Glu uptake decrease as well as inverse operation of spinal Glu transporter to release Glu. In one model, Glu transporter inhibitors further block Glu uptake and enhance the increase in extracellular Glu levels, perhaps leading to dorsal horn neuronal death, increase of spinal GABA contents, activation of inhibitory presynaptic mGluRs, and desensitization of postsynaptic Glu receptors. Glu transporter inhibitors also block neuronal Glu transporter reuptake and/or the Glu/Gln cycle via inhibition of glial Glu transporter, resulting in Glu depletion of synaptic vesicles in primary afferent terminals. In contrast, Glu transporter inhibitors block inverse operation of Glu transporter to release Glu and decrease extracellular Glu levels in another model.