Study of the role of substance P in the regulation of gastric motility and gastric mucosal integrity in rats

Abstract

The effects of substance P (SP) on gastric motility and the involvement of the peptide in the maintenance of gastric mucosal integrity have been studied in rats. Gastric motility: Peripheral administration of SP in a low dose range induced a biphasic effect on basal gastric motility: a transient relaxation followed by an increased gastric tone and phasic contractions. In contrast, with higher doses only a pronounced relaxant effect was observed. Pretreatment with the NK1 receptor antagonist L-733,060 significantly decreased both the inhibitory and stimulatory effects of SP. Atropine reduced both the first and the second phase of the effect of SP while bilateral cervical vagotomy reduced mainly the second phase. The non-selective opioid receptor antagonist naloxone did not influence the effect of SP on the gastric motility. The NOS inhibitor L-NAME slightly reduced the first inhibitory phase and potentiated the stimulation of gastric phasic contraction induced by SP. Central administration of SP did not significantly influence the rat gastric motor activity. Gastroprotection: Supraspinal (intracerebroventricular, i.c.v.) administration of SP dose-dependently inhibited the formation of ethanol-induced ulcers, while intravenously injected SP had no effect. Pretreatment with the NK1 receptor antagonist L-733,060, the NK2 receptor antagonist GR 159897 or the NK3 receptor antagonist SB 222200 reversed the effect of SP. I.c.v. injection of naloxone, beta-funaltrexamine (mu opioid receptor selective antagonist) and endomorphin-2 antiserum antagonized the SP-induced mucosal protection, while the kappa opioid receptor antagonist norbinaltorphimine and the delta opioid receptor antagonist naltrindole were ineffective. Peripheral administration of atropine, NG-nitro-L-arginine (LNNA) and indomethacin also inhibited the effect of SP. In addition, i.c.v. injected SP reversed the significant reduction of gastric mucosal CGRP content following ethanol administration. Peripheral administration of SP failed to inhibit the development of gastric mucosal lesions. In conclusion: Peripherally injected SP induced a biphasic effect on the gastric motility, which is (at least partly) mediated by NK1 receptors and vagal activation. NO may contribute to the inhibitory effect of SP while endogenous opioids are not involved in the effect of the peptide. SP induces central, vagally mediated gastroprotection in rats, and this effect is mediated by tachykinin receptors and (at least partly) by endogenous opioids acting on mu opioid receptors. In the periphery, prostaglandins, NO and CGRP are involved in the mediation of the central gastroprotective effect of SP. The central protective effect of SP seems to be independent from variations of gastric motility.