Inhibition of protein tyrosine kinases attenuated Aβ-fiber-evoked synaptic transmission in spinal dorsal horn of rats with sciatic nerve transection

Peripheral nerve injury leads to the establishment of a novel synaptic connection between afferent A beta-fiber and lamina II neurons in spinal dorsal horn, which is hypothesized to underlie mechanical allodynia. However, how the novel synapses transmit nociceptive information is poorly understood. In the present study, the role of protein tyrosine kinases (PTKs) in A beta-fiber-evoked excitatory postsynaptic currents (EPSCs) recorded in lamina 11 neurons in transverse spinal cord slices of rats was investigated using the whole-cell patch-clamp recording technique. In the slices from sciatic nerve transection (SNT) rats, genistein (50 mu M), a broad-spectrum PTKs inhibitor, or PP2 (20 mu M), a selective Src family tyrosine kinase inhibitor, significantly reduced the amplitude of A beta-fiber EPSCs. In sham-operated rats, however, A beta-fiber EPSCs were insensitive to genistein and PP2. The N-methyl-D-aspartate (NMDA) receptor antagonist AP-V (50 mu M) suppressed A beta-fiber EPSCs in slices from SNT rats. but not from sham-operated rats. Following nerve injury, the slow inward currents elicited by bath application of NMDA (100 mu M) significantly increased at -70 mV. In SNT rats, genistein and PP2 reduced A beta-fiber-evoked EPSCs mediated by NMDA receptor; however, genistein produced little effect on A beta-fiber EPSCs mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. These data suggested that PTKs, especially Src family members, participated in A beta-fiber-evoked synaptic transmission following sciatic nerve injury via potentiation of NMDA receptor function.