DEPRESSION OF PRIMARY AFFERENT-EVOKED RESPONSES BY GR71251 IN THE ISOLATED SPINAL-CORD OF THE NEONATAL RAT

1 The pharmacological profile of GR71251, a new tachykinin receptor an tagonist, and its effect on the responses evoked by stimulation of pri mary afferent fibres were studied in isolated spinal cord preparations of neonatal rats. Potential changes were recorded extracellularly fro m a lumbar ventral root 2 Bath-application of substance P (SP), neurok inin A (NKA) and neurokinin B (NKB) at 0.01-3 muM to the spinal cord i nduced depolarization of the ventral root in normal artificial cerebro spinal fluid (CSF). The NK1 agonist, acetyl-Arg6-septide, and the NK3 agonist, senktide, at 0.01-3 muM, also had potent depolarizing actions whereas two NK2 agonists, beta-Ala8NKA4-10 and Nle10NKA4-10, showed l ittle depolarizing effects at 1 muM. 3 GR71251 (0.3-3 muM) caused a ri ghtward shift of the concentration-response curves for SP, acetyl-Arg6 -septide and NKA with pA2 values of 6.14, 6.75 or 6.70, respectively. The effects of GR71251 were readily reversible within 15-30 min after its removal. By contrast, GR71251 (1-5 muM) had little effect on the d epolarizing responses to NKB and senktide. 4 GR71251 (1-3 muM) did not depress the depolarizing responses to bombesin, neuromedin B and gast rin-releasing peptide in normal artificial CSF. 5 Application of capsa icin to the spinal cord induced a depolarizing response, which was par tially depressed by GR71251 (3-10 muM). 6 In the isolated spinal cord preparation, intense electrical stimulation of a dorsal root evoked a slow depolarizing response of the contralateral ventral root of the sa me segment. A similar slow ventral root depolarization was evoked by e lectrical stimulation of the ipsilateral saphenous nerve in an isolate d spinal cord-saphenous nerve preparation. GR712 51 (0.3-10 muM) dose- dependently depressed these slow ventral root potentials. 7 In the spi nal cord-peripheral nerve preparation, conditioning stimulation of the saphenous nerve evoked an inhibition of the muscle nerve-evoked monos ynaptic reflex lasting about 20 s. The late part of the inhibition was markedly depressed by GR7125 (1-3 muM). 8 The present results indicat e that GR71251 is a potent and specific antagonist for tachykinin rece ptors in the spinal cord. The present study further provides evidence for the involvement of SP and NKA in the slow ventral root depolarizat ion and the prolonged inhibition of monosynaptic reflex that are evoke d by primary afferent stimulation.