Central tachykinin NK3 receptors in the inhibitory action on the rat colonic propulsion of a new tachykinin, PG-KII

The inhibitory action of the natural selective tachykinin NK3 receptor agonist, PG-KII, (pGlu-Pro-Asn-Pro-Asp-Glu-Phe-Val-Gly-Leu-Met-NH2), on colonic propulsion was studied in rats after central administration. Intracerebroventricular injection of PG-KII (0.1, 1, 10 and 100 ng/rat) produced a dose-related inhibition of colonic propulsion, measured as the increase in the mean expulsion time of a 5-mm glass bead placed in the distal colon. At the same doses as PG-KII, the selective tachykinin NK3 receptor agonist, senktide, (succ-[Asp(6)-MePhe(8)] substance P-(6-11)), induced a similar dose-related inhibition. Conversely, substance P (0.1, 1 and 10 mu g/rat), a tachykinin NK1-preferring receptor agonist, had weaker antipropulsive effects, neurokinin A (0.1, 1 and 10 mu g/rat), a tachykinin NK2-preferring receptor agonist, at the highest dose used only slightly inhibited colonic propulsion and neurokinin B (0.1, 1 and 10 mu g/rat), a tachykinin NK1-preferring receptor agonist, left propulsion unchanged. Pretreatment with the selective tachykinin NK3 receptor antagonist, 3-indolycarbonyl-Hyp-Phg-N(me)-Bzl, referred as to R820 (6.2 mu g/rat), prevented PG-KII-induced colonic antipropulsion, whereas the tachykinin NK1 receptor antagonist, (S)-1-(2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)piperidin-3-yl] ethyl)-4-phenyl-1-azoniabicyclo[2.2.2] octane chloride, referred to as SR 140,333 (1 mu g/rat), and the tachykinin NK2 receptor antagonist, ([Tyr(5),D-Trp(6,8,9),Arg(10)] neurokinin A-(4-10)), referred to as Men 10,376 (5 mu g/rat), left it unchanged. These findings show that of the tachykinins tested, PG-KII and senktide are the most potent central inhibitors of colonic propulsion in the rat, suggesting that the central tachykinin NK3 receptor system plays an inhibitory role in modulating colonic transit. As well as confirming the selectivity of PG-KII for tachykinin NK3 receptors, we show that PG-KII provides useful information about the physiological role of central tachykinin NK3 receptors and that glass bead expulsion test is a reliable non-invasive in vivo method for evaluating the tachykinin NK3 receptor selectivity of new synthetic or natural tachykinins. (C) 1999 Elsevier Science B.V. All rights reserved