Evidence for the release of endogenous substance P from intestinal nerves

The desensitization of receptors for substance P in the longitudinal muscle of the guinea-pig ileum has been studied. Receptors for substance P in the muscle became desensitized in the presence of relatively large concentrations of synthetic substance P; a desensitizing concentration of substance P of 7.5×10^-9 M shifted the concentration-response curve for substance P about 20-fold to the right, while a desensitizing concentration of 7.5×10^-8 M shifted the curve about 300-fold to the right. This desensitization appeared specific; concentration-response curves for carbachol, DMPP, 5-HT and bradykinin were not significantly affected by substance P, 7.5×10^-8 M. Furthermore, substance P in concentrations up to 7.5×10^-8 M did not modify transmission from either cholinergic nerves or enteric inhibitory nerves when these were stimulated electrically. However, hyoscine-resistant contractions produced by stimulation of nerves in the ileum at 10 Hz were abolished by exposure to concentrations of substance P of 7.5×10^-9 M or greater, suggesting that these nerves release a substance similar to or identical with substance P. DMPP evoked small hyoscine-resistant contractions of the ileum. These contractions were also antagonised by desensitization of receptors for substance P. Immunohistochemical studies showed substance P-like immunoreactivity in nerve terminals of both the myenteric and submucous plexuses.