Neurokinin B is a preferred agonist for a neuronal substance P receptor and its action is antagonized by enkephalin

Receptor specificity of the substance P-related peptides neurokinin A and neurokinin B was studied in the isolated guinea pig ileum. Substance P and the recently discovered neurokinins elicit contraction of the ileum both directly through action on a muscle cell receptor and indirectly through stimulation of a neuronal receptor, leading to release of acetylcholine, which causes muscle contraction via muscarinic receptors. Two specific assay procedures for the function of the neuronal receptor were developed. The muscular receptor was inactivated either by desensitization with the selective agonist substance P methyl ester or by receptor blockade with the selective antagonist [Arg6, D-Trp7,9, Me-Phe8]substance P-(6-11) hexapeptide. Both procedures revealed that the neuronal receptor is clearly distinct from the muscular receptor, since it exhibits different agonist specificity and is insensitive to antagonists of the muscular receptor. Neurokinin B was found to be the most potent agonist (EC50 = 1 nM) for the neuronal receptor. Furthermore, [D-Ala2, Met5]enkephalinamide inhibited in a naloxone-sensitive manner the effect of neurokinin B mediated via the neuronal receptor. These results suggest that the different mammalian tachykinins can play specific physiological roles by virtue of their distinct receptor specificities.