Role of Capsaicin-Sensitive Sensory Nerves in Gastroprotection against Acid-Independent and Acid-Dependent Ulcerogens

Abstract

Treatment with small doses of topical capsaicin protects the gastric mucosa from the damage by strong irritants but functional ablation of sensory nerves by pretreatment with larger dose of parenteral capsaicin augments the formation of gastric lesions via unknown mechanism. This study was designed to determine the role of gastric acid secretion, mucosal blood flow (GBF) and prostaglandins (PG) generation in the gastroprotection induced by small doses of topical or parenteral capsaicin in rats with intact or capsaicin-deactivated sensory nerves. Gastric lesions were produced in rats with intact sensory nerves (series A) or capsaicin-deactivated nerves (series B) using intragastric (i.g.) application of 100% ethanol, acidified aspirin (ASA) or water immersion and restraint stress (WRS). Pretreatment with i.g. capsaicin (0.12-1.0 mg/kg) in rats with intact sensory nerves (series A) reduced dose-dependently the mucosal damage caused by ethanol, ASA or WRS, the dose inhibiting the lesion area by 50% (ID₅o) being 0.3, 0.5 and 0.7 mg/kg, respectively. This protection was accompanied by a significant rise in gastric mucosal blood flow (GBF). Parenteral application of capsaicin (1.2-10 mg/kg s.c.) that in intact rats dose-dependently increased GBF, also dose-dependently reduced gastric damage induced by ASA or WRS (but not by ethanol), the ID₅₀ being 5 and 3 mg/kg, respectively. The reduction by i.g. capsaicin of ethanol- or WRS-induced mucosal lesions was accompanied by a rise in GBF and this effect was reversed by indomethacin at a dose that suppressed endogenous PG biosynthesis by about 90%, indicating that PG are involved in the protective activities of topical capsaicin. Furthermore, topical and to a lesser extent parenteral capsaicin given to rats with intact or deactivated sensory nerves inhibited gastric acid and pepsin outputs, suggesting that this inhibition could contribute to the capsaicin-induced gastroprotection against acid-dependent mucosal lesions (ASA or WRS). Capsaicin deactiva-tion of sensory nerves aggravated mucosal lesions induced by all three ulcerogens and this effect was accompanied by a marked decrease in GBF. In such capsaicin-deactivated rats, topical capsaicin also reduced ethanol-, ASA- or WRS-induced lesions, while parenteral capsaicin was effective only in the protection against the damage induced by acidified ASA and WRS but not by ethanol. The protection against WRS lesions and accompanying rise in GBF by parenteral capsaicin were also reversed by the pretreatment with indomethacin applied in a dose suppressing the generation of PG. We conclude that capsaicin is capable of protecting gastric mucosa in rats with both intact and capsaicin-deactivated rats and that this protective activity depends, at least in part, upon its hyperemic and antisecretory effects that may be mediated, at least in part, by endogenous release of PG.

Contribution of capsaicin-sensitive sensory neurons to stress-induced increases in gastric tissue levels of prostaglandins in rats

“…Taken together, these observations strongly suggest that CGRP might increase endothelial production of PGI 2 and PGE 2 through NO-mediated activation of COX-1.…”

“…Activated neutrophils play critical roles in the development of the gastric mucosal injury induced by stress (13), nonsteroidal anti-inflammatory drugs (43), and hemorrhagic shock (27) by inducing local inflammation (39,44,45). Because PGI 2 inhibits neutrophil activation by increasing the intracellular concentration of cAMP (22,38), PGI 2 might play a role in the gastric cytoprotection by inhibiting neutrophil activation. Consistent with this hypothesis are our previous findings showing that gastric tissue levels of PGI 2 were significantly increased in rats subjected to water immersion restraint stress (WIR), which contributed to the prevention of stressinduced gastric mucosal injury mainly by inhibiting neutrophil activation (15,16).…”

“…PGE 2 is a well-known gastric cytoprotective agent synthesized in endothelial cells from PGH 2 , a common precursor of PGI 2 (11). Because PGE 2 has been shown to possess biological activities similar to those of PGI 2, (46), activation of capsaicin-sensitive sensory neurons might increase the gastric tissue levels of PGE 2 as well as PGI 2 , thereby contributing to the reduction of gastric mucosal injury.…”

Facilitation by Endogenous Prostaglandins of Capsaicin-Induced Gastric Protection in Rodents through EP2 and IP Receptors

“…Because the gastroprotective action of capsaicin in certain experimental conditions is functionally related with the increase of GMBF (Holzer et al, 1991;Matsumoto et al, 1992;Brzozowski et al, 1996), we examined the gastric hyperemic response to capsaicin in mice and investigated the relation of this action with IP receptors. In addition, we also examined the effect of cicaprost, the PGI 2 agonist on GMBF, to check the absence of IP receptors in IP receptor knockout mice used in the present study.…”

Lafutidine Facilitates Calcitonin Gene-Related Peptide (CGRP) Nerve-Mediated Vasodilation via Vanilloid-1 Receptors in Rat Mesenteric Resistance Arteries

“…Since capsaicin has been shown to stimulate the primary sensory nerves with low concentrations but causes functional ablation of sensory nerves with high concentrations (13,14), a low concentration of 30 pmol was injected with the infusion pump over 10 s. After responses to the first (C 1 ) and second (C 2 ) bolus injection of capsaicin were obtained as the control, the Krebs solution containing methoxamine and guanethidine was switched to Krebs solution containing methoxamine, guanethidine and lafutidine (1 or 10 µM), and then the third (C 3 ) and fourth (C 4 ) injections of capsaicin were carried out. The effect of lafutidine on vasodilator response to capsaicin injection was expressed as the ratio between the vasodilation induced by C 2-4 and C 1 , respectively.…”