Classification of tachykinin receptors in muscularis mucosae of opossum oesophagus

Abstract

1. Muscularis mucosae of the distal oesophagus of the opossum contracts in response to substance P and to a variety of tachykinins. To delineate the nature of the receptors present in this tissue, we evaluated contractile responses to substance P, neurokinin A, neurokinin B, eledoisin and analogues believed to be highly selective for NK-1, NK-2 and NK-3 receptors. In addition, the effects of prolonged exposure to each of these agents (10(-6) M or 10(-5) M) on contractile responses to substance P and to itself were evaluated. Similarly effects of prolonged exposure to the various tachykinins and their analogues on the field-stimulated responses of this muscle were studied. 2. All naturally occurring tachykinins were full agonists and differed in potency (comparing ED50 values) by less than ten fold. In nearly all cases there was cross tachyphylaxis between substance P and the other tachykinins and each reduced tonic responses to field stimulation, a response previously shown to be mediated by a substance P like agent. Eledoisin failed to cause tachyphylaxis under the conditions of these experiments. 3. When highly selective tachykinin analogues were used, only that believed to activate NK-1 receptors was a full agonist. [beta-Ala4,Sar9,MetO2(11)]SP(4-11) was also only slightly less potent than substance P. In contrast, an agonist selective for NK-2 (NK-A) receptors, [Nle10]NKA(4-10), and one selective for NK-3 (NK-B) receptors, [beta-Asp4, MePhe7]NKB(4-10) were unable to produce a response equal to 50% of the maximum even at 10(-5) M. However, all three selective tachykinin analogues reduced responses to substance P but not to carbachol. They usually reduced both phasic and tonic responses to field stimulation. 4. We conclude, based on this and earlier study, that the tachykinin receptors of opossum oesophagus muscularis mucosae recognize all naturally occurring tachykinins but may represent only NK-1 receptors. The ability of analogues selective for other types of tachykinin receptors to reduce responses to substance P raises the possibility that their selectivity depends in part on diminished efficacy rather than totally on diminished affinity at some classes of receptor.