SUBSTANCE-P STIMULATES AND INHIBITS INTESTINAL PERISTALSIS VIA DISTINCT RECEPTORS

The tachykinins substance P (SP) and neurokinin A participate in the n eural control of intestinal peristalsis. This study aimed at elucidati ng the types of tachykinin receptors involved in SP's ability first to stimulate and then to inhibit propulsive activity. Peristalsis in the guinea pig isolated ileum was triggered by fluid-induced distension o f the intestinal wall. Unlike SP, the neurokinin (NK)-1 receptor-selec tive agonist SP methyl ester (1-100 nM) failed to facilitate peristals is but caused a delayed inhibition of peristaltic activity. In contras t, the NK-2 receptor-selective agonist [beta-Ala(8)]-NKA-(4-10) (BANKA , 1-100 nM) stimulated, but did not inhibit, peristalsis. The NK-3 rec eptor-selective agonist succinyl-[Asp(6),N-MePhe(8)]-substance P-(6-11 ) (SENKTIDE, 0.1-10 nM) was most potent in facilitating propulsive act ivity, and only with 10 nM SENKTIDE was a delayed inhibition of perist alsis seen. The receptors responsible for the tachykinin-evoked stimul ation and inhibition of peristaltic activity were further characterize d by use of the NK-1 receptor-selective antagonist 2S,3S)-3-(2-methoxy benzylamino)-2-phenylpiperidine (CP-99,994, 300 nM) and the NK-2 selec tive antagonist N-methyl-N[4-acetylamino-4-phenyl-piperidino-2(3,4 dic hlorophenyl)butyl]-benzamide (SR-48,968, 100 nM), CP-99,994 antagonize d the inhibitory effects of SP (100 nM) and SP methyl ester (100 nM) o n peristalsis but did not alter the facilitation of propulsive motilit y brought about by SP or BANKA (100 nM). Conversely, SR-48,968 (100 nM ) suppressed the ability of SP and BANKA to stimulate peristaltic acti vity but did not attenuate the inhibitory motor effects of SP acid SP methyl ester. These data indicate that tachykinins influence intestina l peristalsis by interaction with NK-1, NK-2 and NK-3 receptors. Activ ation of NK-1 receptors results in inhibition, whereas activation of N K-2 and NK-3 receptors leads to facilitation, of peristaltic motor act ivity.