Abstract

Background: We previously reported that endogenous prostaglandin I₂, generated by a mild irritant, sensitised calcitonin gene related peptide (CGRP) containing sensory nerves and facilitated the release of CGRP and gastric mucosal protection against ethanol. Administration of capsaicin also inhibited ethanol induced gastric mucosal injury through immediate release of CGRP from primary sensory neurones, which is termed the neural emergency system. In the present study, we tested whether endogenous prostaglandin I₂ also modulates the cytoprotective action of capsaicin using prostaglandin I receptor knockout mice (IP^−/−).

Methods: The stomachs of IP^−/− or their wild-type counterparts (IP^+/+), anaesthetised with urethane (1.225 g/kg), were doubly cannulated from the oesophageal and duodenal sides, and the gastric mucosa was perfused (1 ml/min) with physiological saline. Perfusate was changed to 50% ethanol alone, or 50% ethanol containing capsaicin (16∼1600 μM). The injured area was estimated at the end of each perfusion experiment. In some animals, CGRP-(8–37), a CGRP antagonist (0.3 mg/kg), or indomethacin (1 mg/kg) was intravenously injected before perfusion of 50% ethanol containing capsaicin.

Results: Capsaicin inhibited the injured area in a dose dependent manner. Fifty per cent ethanol containing capsaicin (480 μM) immediately increased intragastric levels of CGRP although 50% ethanol alone did not. The protective action of capsaicin (480 μM) against ethanol was completely abolished by intravenous injection of CGRP-(8–37). Indomethacin also inhibited the protective action of capsaicin, and this was accompanied by reduced levels of intragastric CGRP. Intragastric levels of prostaglandin E₂ were not increased by capsaicin treatment but those of 6-keto-prostaglandin F_1α, a metabolite of prostaglandin I₂, were markedly increased. No protective action of capsaicin was observed in IP^−/− which lacked the ability to increase intragastric CGRP levels in response to ethanol containing capsaicin. The CGRP content of the stomach from untreated IP^−/− did not differ from those in IP^+/+. Capsaicin (160 μM) together with intragastric perfusion of beraprost sodium (PGI₂ analogue, 2.5 μg/ml) showed enhanced protection against ethanol induced injury. This enhanced protection was completely blocked by intravenous injection of CGRP-(8–37).

Conclusions: The present results suggest that endogenous prostaglandin I₂ enhances the protective action of the capsaicin mediated neural emergency system against ethanol induced gastric mucosal injury through enhancement of CGRP release.