Central, but not peripheral administration of substance P induces opioid-mediated gastroprotection in the rat

Introduction: Although the gastrointestinal effects of the tachykinin substance P (SP) have been studied for a long period, its role in the regulation of gastric mucosal integrity has not been fully clarified. Both aggravation of ethanol-induced damage and lack of effect have been reported after peripheral injection of SP in rats (Evangelista et al., 1987; 1991; Karmeli et al., 1991). In contrast, centrally injected SP reduced cold-restraint stress-induced gastric ulcers (Hernandez et al., 1983). The aim of our study was 1) to analyze the effect of SP in an acid-independent ulcer model in rats, and 2) to clarify, whether the endogenous opioid system is involved in the SP-induced mucosal protection. Methods: The ethanol-ulcer model was used. After 24h starvation, male Wistar rats were given 0.5ml acidified ethanol orally. The mucosal lesions were evaluated 1h later. SP was given either intracerebroventricularly (i.c.v.) or intravenously (i.v.). Results: 1) I.c.v. injected SP (9.3–37pmol/rat) dose-dependently inhibited the formation of ethanol-induced ulcers. 2) In contrast, intravenous SP (0.3–7 nmol/kg i.v.) failed to induce gastroprotective effect. 3) The central gastroprotective effect of SP was inhibited by the NK1-receptor antagonist L-733,060 (1.1 nmol i.c.v.). 4) The non-selective opioid receptor antagonist naloxone (27 nmol i.c.v.) antagonized the effect of SP as well, while the κ opioid receptor antagonist norbinaltorphimine (14 nmol i.c.v.) and the δ opioid receptor antagonist naltrindole (5 nmol i.c.v.) had no effect. 5) Pretreatment with endomorphin-2 antiserum (i.c.v.) also inhibited the SP-induced central gastroprotection. Conclusions: Our results suggest that SP given centrally, but not peripherally induces gastroprotection in rats, and this effect is mediated by NK1-receptors and endogenous opioids (presumably endomorphins) acting on µ-opioid receptors. The work was supported by ETT 341/2009 from the Scientific Health Council and National Office for Research and Technology (NKTH).