Neural actions of several substance P antagonists in the rat spinal cord

Four substance P (SP) antagonists were tested on anaesthetized rats, by injecting 8 microgram amounts into the spinal cord (T8-T9), and by observing their effects on the hypothalamo-neurohypophysial responses to a presumably painful stimulus, the superfusion of the hepatic portal vein with 1 microM bradykinin. Only two antagonists, the new D-Pro4,D-Trp7,9,10,Val8-SP4-11 and D-Pro4,D-Trp7,9,10-SP4-11 were capable of inhibiting the responses by 50-60%, the former compound having 3 times less agonistic activity. The results suggest that substitution of the aromatic phenylalanine by the non-polar valine in position 8 may significantly improve the overall characteristics of neurally active SP antagonists.