Depression of windup of spinal neurons in the neonatal rat spinal cord in vitro by an NK3 tachykinin receptor antagonist

The effects of the NK3 tachykinin receptor antagonist SR 142801 on synaptic transmission and spike windup induced by trains of stimuli applied to a do rsal root were investigated with intra- and extracellular recording from th e neonatal rat spinal cord in vitro. SR 142801 (10 muM) reduced the depolar ization (recorded from lumbar ventral roots) induced by senktide (an NK3 ag onist) more strongly than the one evoked by substance P methyl ester (SPMeO ; an NK1 agonist). Nevertheless, after a long (>2 h) application time, SR 1 42801 largely depressed the response to SPMeO as well. When NK1 or NK3 rece ptors were blocked by >50% in the presence of SR 142801, there was also a s ignificant reduction in the cumulative depolarization induced by repeated s timuli to a single dorsal root. This blocking action by SR 142801 was also observed in the presence of the N-methyl-D-aspartate (NMDA) receptor antago nist D-aminophosphonovalerate (APV) and the calcium channel blocker nifedip ine. Intracellular data from lumbar motoneurons showed that the spike windu p was the first and most sensitive target for the SR 142801 blocking effect . Increasing stimulus strength to dorsal root fibers could partly surmount such a block. SR 142801 per se had no direct action on fast synaptic transm ission, membrane potential, or input resistance. These findings indicate th at SR 142801 could lead to an early, large reduction in the windup of actio n potential discharge by motoneurons, suggesting its ability to suppress th e reflex component of central sensitization evoked by repeated dorsal root stimuli.