Central tachykinin NK 3 receptors in the inhibitory action on the rat colonic propulsion of a new tachykinin, PG-KII

Abstract

The inhibitory action of the natural selective tachykinin NK 3 receptor agonist, PG-KII, (pGlu-Pro-Asn-Pro-Asp-Glu-Phe-Val-Gly-Leu-Met-NH 2), 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 NK 3 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 μg/rat), a tachykinin NK 1-preferring receptor agonist, had weaker antipropulsive effects, neurokinin A (0.1, 1 and 10 μg/rat), a tachykinin NK 2-preferring receptor agonist, at the highest dose used only slightly inhibited colonic propulsion and neurokinin B (0.1, 1 and 10 μg/rat), a tachykinin NK 3-preferring receptor agonist, left propulsion unchanged. Pretreatment with the selective tachykinin NK 3 receptor antagonist, 3-indolycarbonyl-Hyp-Phg- N(me)-Bzl, referred as to R820 (6.2 μg/rat), prevented PG-KII-induced colonic antipropulsion, whereas the tachykinin NK 1 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 μg/rat), and the tachykinin NK 2 receptor antagonist, ([Tyr 5, d-Trp 6,8,9, Arg 10] neurokinin A-(4–10)), referred to as Men 10,376 (5 μg/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 NK 3 receptor system plays an inhibitory role in modulating colonic transit. As well as confirming the selectivity of PG-KII for tachykinin NK 3 receptors, we show that PG-KII provides useful information about the physiological role of central tachykinin NK 3 receptors and that glass bead expulsion test is a reliable non-invasive in vivo method for evaluating the tachykinin NK 3 receptor selectivity of new synthetic or natural tachykinins.