I.Th. Lippe

Stimulation of afferent nerve endings by intragastric capsaicin protects against ethanol-induced damage of gastric mucosa.

Ablation of capsaicin-sensitive afferent neurons enhances experimentally induced ulceration in the rat gastric mucosa, which suggests that these neurons are involved in gastric mucosal protection. To provide direct evidence for such a function it was investigated whether stimulation of afferent nerve endings by the intragastric administration of capsaicin could counteract the ulcerogenic effect of 25% ethanol. Capsaicin (3.2-640 microM), administered together with ethanol, inhibited the development of haemorrhagic lesions in a concentration-dependent fashion but did not alter the ethanol-induced fall in the gastric potential difference. This suggests that capsaicin does not prevent ethanol from damaging gastric epithelial cells but can counteract the vascular lesions caused by ethanol. The anti-lesion effect of intragastric capsaicin was absent in adult rats which had been treated with a high dose of systemic capsaicin as neonates in order to achieve a permanent degeneration of unmyelinated afferent neurons. It would appear, therefore, that intragastric capsaicin reduces lesion formation by an action on afferent neurons. The protective effect of intragastric capsaicin was not altered following acute subdiaphragmatic vagotomy, acute removal of the coeliac-superior mesenteric ganglion complex, acute bilateral ligation of the adrenal glands, or pretreatment of the rats with atropine or guanethidine. These findings indicate that stimulation of afferent neurons by intragastric capsaicin affords protection of the rat gastric mucosa against ethanol-induced damage. As the autonomic nervous system is not involved gastroprotection appears to represent a local effector function of sensory nerve endings in the stomach.

Afferent nerve-mediated protection against deep mucosal damage in the rat stomach☆

Intragastric capsaicin protects against ethanol-induced gross mucosal lesion formation by stimulation of afferent nerve endings in the rat stomach. The aims of the present study were to examine histologically the protective effect of capsaicin and to test whether this effect is related to changes in mucosal eicosanoid formation and mucosal blood flow. Intragastric capsaicin (160 microM) significantly reduced gross mucosal lesion formation induced by 25% ethanol. Light microscopy revealed that the depth of erosions was attenuated likewise. However, capsaicin did not prevent ethanol from causing superficial damage to the mucosa as observed by light and scanning electron microscopy. The protective action of capsaicin against ethanol remained unchanged by a dose of indomethacin that reduced the ex vivo formation of prostaglandin E2 and 6-oxo-prostaglandin F1 alpha in the gastric mucosa by about 90%. Capsaicin alone did not affect the ex vivo formation of these prostaglandins and of leukotriene C4. Intragastric capsaicin (160 microM) enhanced gastric mucosal blood flow by 89% as measured by the hydrogen gas clearance technique. This effect was also observed when capsaicin was administered together with 25% ethanol. These data indicate that afferent nerve stimulation by intragastric capsaicin protects against deep mucosal damage in response to ethanol, an effect that seems related to an increase in mucosal blood flow but not to eicosanoid formation.

Intragastric capsaicin protects against aspirin-induced lesion formation and bleeding in the rat gastric mucosa

Previous work has indicated that capsaicin-sensitive afferent neurons are involved in gastric mucosal defense mechanisms. The present study investigated whether stimulation of these neurons by intragastric administration of capsaicin would protect against aspirin-induced mucosal damage in the luminally perfused rat stomach. Capsaicin (25-640 microM), administered together with acidified (pH 1.5) aspirin (25 mM), inhibited macroscopically visible lesion formation and gastric bleeding in a concentration-dependent fashion. Capsaicin (160 microM) also attenuated the aspirin-induced fall in the gastric potential difference. An inhibitory effect of capsaicin (160 microM) on aspirin-induced gastric injury was also seen by light and scanning electron microscopy. Aspirin alone caused a vast ablation of the gastric surface epithelium, resulting in exposure of the lamina propria. In the presence of capsaicin, the depth of mucosal injury, the area totally deprived of surface epithelial cells, and the severity of surface desquamation were diminished. As capsaicin is a selective stimulant of thin afferent neurons, it would appear that these neurons participate in mechanisms of gastric defense against aspirin injury. Prevention of hemorrhagic damage seems to be the primary effect of afferent nerve-mediated gastroprotection, although injury to the surface epithelium is also reduced to some degree.

Inhibition of gastrointestinal transit due to surgical trauma or peritoneal irritation is reduced in capsaicin-treated rats

Treatment of newborn rats with capsaicin (0.16 mmol/kg) is known to cause a permanent degeneration of mainly unmyelinated afferent neurons. In this study, postoperative ileus and ileus produced by peritoneal irritation with iodine were investigated in adult rats treated with capsaicin as neonates. It was found that in capsaicin-treated rats both forms of ileus, measured as inhibition of gastrointestinal transit, were significantly reduced as compared with vehicle-treated control animals. Adrenoceptor blockade in untreated rats reduced the ileus in response to peritoneal irritation to approximately the same degree as treatment with capsaicin. In capsaicin-treated rats, however, adrenoceptor blockade was without effect on the irritation-induced ileus. It is concluded that ileus in response to surgery or peritoneal irritation is due, at least in part, to activation of a neural reflex. The afferent limb of this reflex may be constituted by capsaicin-sensitive nerve fibers, whereas the efferent limb seems to involve sympathetic adrenergic neurons.

Participation of capsaicin-sensitive afferent neurons in gastric motor inhibition caused by laparotomy and intraperitoneal acid

Stimulation of somatic or visceral nociceptors causes changes in gastrointestinal motor activity and blood pressure. The present study examined the possible participation of capsaicin-sensitive afferent and noradrenergic efferent neurons in the blood pressure and gastric motor responses to laparotomy and intraperitoneal injection of capsaicin or hydrochloric acid in the rat. Gastric motor activity was measured by recording the intragastric pressure of phenobarbital-anaesthetized rats via an oesophageal catheter. Laparotomy as well as intraperitoneal injection of capsaicin (33 and 330 microM) or hydrochloric acid (30 mM) caused a transient reduction of gastric motor activity stimulated by intravenous infusion of bombesin (200 pmol/min) and a brief fall of blood pressure (depressor effect). The depressor effect of laparotomy was followed by prolonged hypertension. Defunctionalization of capsaicin-sensitive afferent neurons by systemic pretreatment of rats with capsaicin (0.4 mmol/kg) prevented the depressor effect and gastric motor inhibition elicited by laparotomy, intraperitoneal capsaicin (33 microM) or intraperitoneal hydrochloric acid (30 mM). However, the effects of 330 microM capsaicin on blood pressure and gastric motility were only partially reduced by capsaicin pretreatment. Blockade of noradrenergic sympathetic neurons by pretreating rats with guanethidine (0.225 mmol/kg) prevented the gastric motor inhibition and depressor effects of laparotomy and intraperitoneal injection of hydrochloric acid (30 mM). The inhibition of gastric motility caused by capsaicin (33 and 330 microM) was only partially reduced by guanethidine pretreatment. The secondary hypertension following the depressor effect of intraperitoneal capsaicin or hydrochloric acid was enhanced in guanethidine-pretreated rats whereas the prolonged hypertension induced by laparotomy was left unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuropeptide Y inhibits excitatory enteric neurons supplying the circular muscle of the guinea pig small intestine

The effect of neuropeptide Y on the motor activity of the circular and longitudinal muscle of the guinea pig small intestine was investigated. Neuropeptide Y (0.3-30 nM) inhibited, in a concentration-dependent manner, the ascending enteric reflex contraction of the circular muscle; both the cholinergic and noncholinergic component of the ascending enteric reflex were suppressed. Neuropeptide Y also blocked nerve-mediated phasic contractions of the circular muscle, induced by dimethylphenylpiperazinium or ceruletide, and abolished the peristaltic movements of the small intestine. Nerve-mediated cholinergic and noncholinergic contractions of the longitudinal muscle, induced by electrical field stimulation, were only slightly depressed by neuropeptide Y. Further analysis showed that neuropeptide Y did not act directly on intestinal muscle but interrupted excitatory pathways of the enteric nervous system. The effect of neuropeptide Y did not involve activation of alpha-adrenoceptors, opioid receptors, or P1 purinoceptors or the release of endogenous factors stimulating these receptors. These findings suggest a possible physiologic role of neuropeptide Y as a nonnoradrenergic inhibitory transmitter involved in the enteric nervous control of intestinal circular muscle activity.

Capsaicin‐sensitive extrinsic afferents are involved in acid‐induced activation of distinct myenteric neurons in the rat stomach

Abstract Challenge of the rat gastric mucosa with 0.5 mol L−1 HCl activates nitrergic neurons in the myenteric plexus as visualized by c‐Fos immunohistochemistry. In the present study, we characterized the activated neurons more extensively by their chemical coding and investigated whether a neural pathway that involves capsaicin‐sensitive extrinsic afferents and/or cholinergic neurons transmitting via nicotinic receptors contributes to the activation of myenteric neurons. In multiple labelling experiments, c‐Fos was examined for co‐localization with nitric oxide synthase (NOS), vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), enkephalin (ENK), gastrin‐releasing peptide (GRP), substance P (SP), calbindin D‐28k (CALB) and neurofilament 145 (NF 145). All c‐Fos‐positive neurons were immunoreactive for NOS, VIP, NPY and NF 145, but not for SP, ENK, GRP and CALB. Nerve fibres co‐expressing NOS, VIP and NPY were predominantly found in the external muscle layer and in the muscularis mucosae but rarely in the mucosa. Pre‐treatment with capsaicin or hexamethonium or a combination of both pre‐treatments reduced HCl‐induced c‐Fos expression by 54, 66 and 63%, respectively. Acid challenge of the stomach, therefore, leads to activation of presumably inhibitory motor neurons responsible for muscle relaxation. Activation of these neurons is partly mediated by capsaicin‐sensitive afferents and involves ganglionic transmission via nicotinic receptors.

Role of Peptidergic Sensory Neurons in Gastric Mucosal Blood Flow and Protection

The present findings have revealed a new aspect of how mechanisms of gastric mucosal resistance to injury are called into effect and are coordinated by the nervous system. Capsaicin‐sensitive sensory neurons in the stomach play a physiological role in monitoring acid influx into the superficial mucosa. Once activated, they strengthen gastric mucosal defense against deep injury, with a key process in this respect being an increase in blood flow through the gastric mucosa. This concept opens up completely new perspectives in the physiology and pathophysiology of the gastric mucosa if we consider that the long‐term integrity of the gastric mucosa may be under the subtle control of acid‐sensitive sensory neurons and that, vice versa, improper functioning of these neural control mechanisms may predispose to gastric ulcer disease.

EP4 receptor prevents endotoxin‐induced neutrophil infiltration into the airways and enhances microvascular barrier function

Pulmonary vascular dysfunction is a key event in acute lung injury. We recently demonstrated that PGE2, via activation of E‐prostanoid (EP)4 receptors, strongly enhances microvascular barrier function in vitro. The aim of this study was to investigate the beneficial effects of concomitant EP4 receptor activation in murine models of acute pulmonary inflammation.

Density distribution of guinea pig myenteric plexus nerve endings containing immunoreactive substance P

The present study was performed to investigate how myenteric plexus nerve endings containing substance P are distributed in sucrose density gradients in relation to nerve endings capable of taking up 3H-acetylcholine or 14C-noradrenaline. The peak of substance P-immunoreactivity (ISP) was found at a density of 1.157 +/- 0.001 g X ml-1, that of 3H-radioactivity at 1.160 +/- 0.002 and that of 14C-radioactivity at 1.162 +/- 0.002 g X ml-1 (mean +/- SEM, N = 6); there was considerable overlap. In a second set of experiments, the resuspended P2-pellet was layered upon a discontinuous density gradient consisting of 0.6, 1.0, 1.2 and 1.4 M sucrose. Nine fractions were recovered. There was a 2.5-3.4-fold increase in the relative specific activity of ISP in the 1.2 M fraction (density = 1.154 g X ml-1) and the adjoining interfaces. Conventional electron microscopy showed that synaptosomal elements were present in the transmitter-enriched fractions. It is concluded that the substance P-containing nerve endings of the guinea pig myenteric plexus co-distribute (and may be co-purified with) nerve endings utilizing noradrenaline or acetylcholine on sucrose density gradients.