Presynaptic kainate receptors regulate spinal sensory transmission

Small diameter dorsal root ganglion (DRG) neurons, which include cells that transmit nociceptive information into the spinal cord, are known to expres s functional kainate receptors. It is well established that exposure to kai nate will depolarize C-fiber afferents arising from these cells. Although t he role of kainate receptors on sensory afferents is unknown, it has been h ypothesized that presynaptic kainate receptors may regulate glutamate relea se in the spinal cord. Here we show that kainate, applied at low micromolar concentrations in the presence of the AMPA-selective antagonist (RS)-4-(4- aminophenyl)-1,2-dihydro-1- methyl-2-propyl-carbamoyl-6,7-methylenedioxypht halazine, suppressed spontaneous NMDA receptor-mediated EPSCs in cultures o f spinal dorsal horn neurons. In addition, kainate suppressed EPSCs in dors al horn neurons evoked by stimulation of synaptically coupled DRG cells in DRG-dorsal horn neuron cocultures. Interestingly, although the glutamate re ceptor subunit 5-selective kainate receptor agonist (RS)-2-alpha -amino-3-( 3-hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid (ATPA) (2 muM) was able to suppress DRG-dorsal horn synaptic transmission to a similar extent as k ainate (10 muM), it had no effect on excitatory transmission between dorsal horn neurons. Agonist applications revealed a striking difference between kainate receptors expressed by DRG and dorsal horn neurons. Whereas DRG cel l kainate receptors were sensitive to both kainate and ATPA, most dorsal ho rn neurons responded only to kainate. Finally, in recordings from dorsal ho rn neurons in spinal slices, kainate and ATPA were able to suppress NMDA an d AMPA receptor-mediated EPSCs evoked by dorsal root fiber stimulation. Tog ether, these data suggest that kainate receptor agonists, acting at a presy naptic locus, can reduce glutamate release from primary afferent sensory sy napses.