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).
