Involvement of Capsaicin-Sensitive Sensory Neurons in Stress-Induced Gastroduodenal Mucosal Injury in Rats

The pathogenesis of stress-induced gastroduodenal mucosal injury is complex and incompletely understood. The aim of this investigation was to examine the involvement of gastric and duodenal capsaicin-sensitive neurons in mucosal damage associated with water-restraint stress (WRS) in rats. Following WRS, gastroduodenal mucosal injury was quantitated by macroscopic and microscopic methods. Calcitonin gene-related peptide (CGRP) content was measured by radioimmunoassay. WRS-induced mucosal erosive injury in the stomach and duodenum (40.9 ± 4.2 and 5.1 ± 0.6 mm², respectively) was reduced significantly (by 88% and 67%, respectively) by acute intragastric capsaicin administration prior to WRS. In contrast, sensory denervation by chronic capsaicin significantly increased the area of gastric injury and duodenal damage. WRS alone caused a significant reduction (by 52% and –35%, respectively) in gastric and duodenal CGRP content, which was prevented by acute capsaicin treatment. The data suggest that gastric and duodenal sensory neurons and CGRP are involved in the pathogenesis of stress-induced mucosal injury to the stomach and duodenum.     

Mechanism of intragastric nicotine protection against ethanol-induced gastric injury

To elucidate the mechanism of intragastric nicotine protection against ethanol-induced gastric mucosal injury seen in a previous report and in our preliminary study, the following studies were performed. Rats were pretreated with naloxone (8 mg/kg intraperitoneal, 0.5 hr prior to study) to block opiate receptors; or capsaicin (125 mg/kg subcutaneous 10 days prior to study) to denervate the afferent sensory fibers; or indomethacin (2.5 mg/kg intragastric or 5 mg/kg subcutaneous, 1 hr prior to study) to inhibit endogenous prostaglandin synthesis. At 1-hr intervals, nicotine (4 mg/kg) or vehicle and 40% ethanol were then given intragastrically. Total gastric corpus mucosal lesion length was measured unbiasedly. In separate studies, gastric mucosal blood flow (GMBF) was assessed by hydrogen gas clearance before and after intragastric nicotine or vehicle; luminal mucus volume, gastric juice volume, and acid output were measured 1 hr after either intragastric nicotine or vehicle administration. The results showed that the acute protective effect of intragastric nicotine was associated with a significantly larger luminal mucus volume. It was not blocked by naloxone, capsaicin, or indomethacin. There was no increase in GMBF. The larger gastric residual volume did not account for the protection. We conclude that the mechanism mediating nicotine protection is unique and is independent of opiate receptors, capsaicin-sensitife afferent sensory nerve fibers, endogenous prostaglandin generation, or dilution of the injurious agent. The increase in luminal gastric mucus volume may contribute to the protective effect of intragastric nicotine against gastric mucosal injury produced by 40% ethanol.     

Laparotomy-induced gastric protection against ethanol injury is mediated by capsaicin-sensitive sensory neurons

Laparotomy significantly attenuates ethanol-induced gastric mucosal lesions in the rat. The effects of sensory denervation by capsaicin, indomethacin, atropine, guanethidine, and hexamethonium on laparotomy-induced protection were studied in the rat. Gastric mucosal injury was induced by the intragastric instillation of 1 mL of 75% ethanol. The laparotomy-induced protection against ethanol injury was abolished by sensory denervation by capsaicin (total dose, 125 mg/kg, SC) and also by pretreatment with indomethacin (5 mg/kg, SC). In contrast, pretreatment with atropine (0.5 mg/kg, IP), guanethidine (total dose, 20 mg/kg, SC), or hexamethonium (20 mg/kg, IP) had no significant effect on laparotomy-induced protection. These data indicate that capsaicin-sensitive sensory afferent neurons, but not cholinergic or adrenergic autonomic neurons, mediate laparotomy-induced protection against ethanol injury. The hypothesis is put forward that the protective response to laparotomy arises from a somatovisceral and/or viscerovisceral axon reflex of capsaicin-sensitive afferent neurons. Prostaglandins might play a mediator role in the activation by laparotomy of somatic and/or visceral branches of the afferent neurons.     

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.     

Effect of capsaicin and chilli on ethanol induced gastric mucosal injury in the rat.

Capsaicin, the pungent ingredient of chilli, is gastroprotective against experimental gastric injury when given intragastrically. Epidemiological and clinical data suggest that chilli ingestion may have a beneficial effect on human peptic ulcer disease. This study showed a gastroprotective effect of intragastric capsaicin, in doses of 2 and 5 mg, on ethanol induced gastric mucosal injury using macroscopic, histological, scanning electron microscopic, and biochemical indices. Subcutaneous administration of 2 mg of capsaicin had the same gastroprotective effect as intragastric administration. Acute intragastric administration and chronic ingestion of chilli powder in doses comparable with that consumed in humans (up to 200 mg in single doses or 200 mg daily for four weeks) likewise protected the gastric mucosa. Both the mucosa and gastric juice had higher mucus contents when capsaicin or chilli rather than saline or solvent was used before ethanol challenge. In control animals capsaicin also increased gastric juice mucus content although the mucosal content was unaffected. Increased gastric mucus production may therefore be one mechanism by which capsaicin and chilli exert their gastroprotective effect although an alternative explanation is that the reduction in mucosal mucus depletion is secondary to the protective effect of capsaicin and chilli.     

Sensory Denervation Reduces Visceral Hypersensitivity in Adult Rats Exposed to Chronic Unpredictable Stress: Evidences of Neurogenic Inflammation

The purpose of this study is to provide evidence of neurogenic inflammation in chronic unpredictable stressed rats with the changes of visceral sensitivity, number of mast cells, and close proximity among mast cell-nerve-blood vessels. We found that (1) capsaicin denervation blocked stress-induced increase of visceral sensitivity, while doxantrazole presented a partial blocking; (2) capsaicin denervation blocked stress-induced enhancement of the proximity of mast cell-nerve fiber-blood vessels and blood vessel damage, while doxantrazole showed no effects on these; (3) doxantrazole blocked stress-induced increases of the MPO activity, the number and the degranulation of mast cells in the colon; (4) sensory denervation and doxantrazole had no effects on stress-induced behavioral inhibition. These results suggest that capsaicin-sensitive sensory fibers play a key role in stress-induced visceral hypersensitivity and the ultrastructural changes, mast cells play an important role in the generation of stress-induced colon inflammation.     

Morphine potentiation of ethanol-induced gastric mucosal damage in the rat. Role of local sensory afferent neurons

Local capsaicin-sensitive sensory afferent neurons may regulate the ability of the gastric mucosa to withstand challenge. Since opioids can modulate the activity of afferent neurones by actions at peripheral sites, the effects of morphine on gastric mucosal damage has been investigated in the rat. Morphine (3-9 mg.kg-1 i.v.) dose-dependently augmented the damage induced by a 5-min intragastric challenge with ethanol (25%-100%), as assessed by macroscopic and histological evaluation. These effects of morphine were significantly inhibited by the opioid antagonists naloxone and the peripherally acting N-methylnalorphine. Pretreatment of rats with capsaicin 2 weeks before the study to induce functional ablation of primary afferent neurons likewise significantly augmented the damage induced by ethanol. Both morphine administration and capsaicin pretreatment substantially augmented histologically assessed damage to the glandular mucosa and enhanced deep hemorrhagic damage following challenge with the low ethanol concentrations, with the appearance of macroscopically distinct antral damage. The enhanced damage induced by 50% ethanol in capsaicin-pretreated rats was not further enhanced by morphine administration, suggesting actions on a common mechanism. These findings support a pathophysiological role for activation of local opioid-sensitive afferent neurons in the modulation of mucosal injury following challenge.     

Protective role of vanilloid receptor type 1 in HCl‐induced gastric mucosal lesions in rats

Background: Effects of vanilloid‐receptor agonists and antagonists on HCl‐induced gastric lesions in rats were investigated to elucidate the role of vanilloid receptor type 1 (VR1) in gastric mucosal defense mechanisms. Methods: Gastric lesions in rats were evaluated after intragastric administration of 0.6?N HCl. The localization of VR1 in the stomach was investigated immunohistochemically. Results: Intragastric administration of capsaicin inhibited the formation of gastric lesions in a dose‐dependent manner (0.1–2.5?mg/kg). The functional VR1 antagonists ruthenium red and capsazepine markedly aggravated HCl‐induced gastric lesions in rats. The gastroprotective effect of capsaicin was attenuated by ruthenium red or capsazepine. It is reported that resiniferatoxin, [6]‐gingerol and lafutidine are compounds that activate VR1 and/or capsaicin‐sensitive afferent neurons. These compounds significantly inhibited the formation of HCl‐induced gastric lesions, and their gastroprotective effects were inhibited by treatment with ruthenium red. The immunohistochemical studies revealed that nerve fibers expressing VR1 exist along gastric glands in the mucosa, around blood vessels in the submucosa, in the myenteric plexus, and in the smooth muscle layers, especially the circular muscle layer. Conclusion: The results of this study suggest that VR1 plays a protective role in the gastric defensive mechanism in rats.     

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.     

Grapefruit-seed extract attenuates ethanol-and stress-induced gastric lesions via activation of prostaglandin, nitric oxide and sensory nerve pathways

AIM: Grapefruit-seed extract (GSE) containing flavonoids, possesses antibacterial and antioxidative properties but whether it influences the gastric defense mechanism and gastroprotection against ethanol- and stress-induced gastric lesions remains unknown. METHODS: We compared the effects of GSE on gastric mucosal lesions induced in rats by topical application of 100% ethanol or 3.5 h of water immersion and restraint stress (WRS) with or without (A) inhibition of cyclooxygenase (COX)-1 activity by indomethacin and rofecoxib, the selective COX-2 inhibitor, (B) suppression of NO-synthase with L-NNA (20 mg/kg ip), and (C) inactivation by capsaicin (125 mg/kg sc) of sensory nerves with or without intragastric (ig) pretreatment with GSE applied 30 min prior to ethanol or WRS. One hour after ethanol and 3.5 h after the end of WRS, the number and area of gastric lesions were measured by planimetry, the gastric blood flow (GBF) was assessed by H2-gas clearance technique and plasma gastrin levels and the gastric mucosal generation of PGE2, superoxide dismutase (SOD) activity and malonyldialdehyde (MDA) concentration, as an index of lipid peroxidation were determined. RESULTS: Ethanol and WRS caused gastric lesions accompanied by the significant fall in the GBF and SOD activity and the rise in the mucosal MDA content. Pretreatment with GSE (8-64 mg/kg i g) dose-dependently attenuated gastric lesions induced by 100% ethanol and WRS; the dose reducing these lesions by 50% (ID50) was 25 and 36 mg/kg, respectively, and this protective effect was similar to that obtained with methyl PGE2 analog (5 μg/kg i g). GSE significantly raised the GBF, mucosal generation of PGE2, SOD activity and plasma gastrin levels while attenuating MDA content. Inhibition of PGE2 generation with indomethacin or rofecoxib and suppression of NO synthase by L-NNA or capsaicin denervation reversed the GSE-induced protection and the accompanying hyperemia. Co-treatment of exogenous calcitonine gene-related peptide (CGRP) with GSE restored the protection and accompanying hyperemic effects of GSE in rats with capsaicin denervation. CONCLUSION: GSE exerts a potent gastroprotective activity against ethanol and WRS-induced gastric lesions via an increase in endogenous PG generation, suppression of lipid peroxidation and hyperemia possibly mediated by NO and CGRP released from sensory nerves.     

Protective role of vanilloid receptor type 1 in HCl-induced gastric mucosal lesions in rats

BACKGROUND: Effects of vanilloid-receptor agonists and antagonists on HCl-induced gastric lesions in rats were investigated to elucidate the role of vanilloid receptor type 1 (VR1) in gastric mucosal defense mechanisms. METHODS: Gastric lesions in rats were evaluated after intragastric administration of 0.6 N HCl. The localization of VR1 in the stomach was investigated immunohistochemically. RESULTS: Intragastric administration of capsaicin inhibited the formation of gastric lesions in a dose-dependent manner (0.1-2.5 mg/kg). The functional VR1 antagonists ruthenium red and capsazepine markedly aggravated HCl-induced gastric lesions in rats. The gastroprotective effect of capsaicin was attenuated by ruthenium red or capsazepine. It is reported that resiniferatoxin, [6]-gingerol and lafutidine are compounds that activate VR1 and/or capsaicin-sensitive afferent neurons. These compounds significantly inhibited the formation of HCl-induced gastric lesions, and their gastroprotective effects were inhibited by treatment with ruthenium red. The immunohistochemical studies revealed that nerve fibers expressing VR1 exist along gastric glands in the mucosa, around blood vessels in the submucosa, in the myenteric plexus, and in the smooth muscle layers, especially the circular muscle layer. CONCLUSION: The results of this study suggest that VR1 plays a protective role in the gastric defensive mechanism in rats.     

Effect of neonatal capsaicin treatment on haemodynamics and renal function in cirrhotic rats

BACKGROUND: Mechanisms underlying abnormalities of circulation and renal function in cirrhosis are not completely understood. Our previous study revealed that primary afferent denervation by neonatal capsaicin treatment prevented the development of hyperdynamic circulation in portal hypertensive and cirrhotic rats. AIMS: The present study aimed to clarify the role of capsaicin sensitive nerves in the development of renal dysfunction and ascites formation in cirrhosis. METHODS: Rat pups were injected with capsaicin (50 mg/kg) or vehicle and allowed to grow. When they reached adulthood, cirrhosis was induced by bile duct ligation while controls received sham operation. Cardiac output and regional blood flows were measured by radioactive microspheres, glomerular filtration rate by (3)H inulin clearance, and urine volume, sodium excretion, and ascites formation were determined. Immunohistochemical staining for Fos in the brain stem cardiovascular regulatory nuclei, the nucleus of the solitary tract, and ventrolateral medulla was measured as an index of central neuronal activation. RESULTS: Increased cardiac output and renal blood flow, and decreased systemic vascular resistance, arterial pressure, renal vascular resistance, and glomerular filtration rate, as well as ascites, were found in vehicle treated cirrhotic rats. Neonatal capsaicin treatment completely blocked the development of hyperdynamic circulation and ascites, and improved renal function in cirrhotic rats. This was associated with complete abrogation of brain stem neuronal activation in capsaicin treated cirrhotic rats. CONCLUSIONS: These results indicate that intact primary afferent innervation is necessary for the development of not only the hyperdynamic circulation but also the renal dysfunction and ascites formation characteristic of cirrhosis.     

Ablation of capsaicin sensitive afferent nerves impairs defence but not rapid repair of rat gastric mucosa.

Capsaicin sensitive afferent neurones have previously been reported to play a part in gastric mucosal protection. The aim of this study was to investigate whether these nociceptive neurones strengthen mucosal defence against injury or promote rapid repair of the damaged mucosa, or both. This hypothesis was examined in anaesthetised rats whose stomachs were perfused with ethanol (25 or 50% in saline, wt/wt) for 30 minutes. The gastric mucosa was inspected 0 and 180 minutes after ethanol had been given at the macroscopic, light, and scanning electron microscopic level. Rapid repair of the ethanol injured gastric mucosa (reduction of deep injury, partial re-epithelialisation of the denuded surface) took place in rats anaesthetised with phenobarbital, but not in those anaesthetised with urethane. Afferent nerve ablation as a result of treating rats with a neurotoxic dose of capsaicin before the experiment significantly aggravated ethanol induced damage as shown by an increase in the area and depth of mucosal erosions. Rapid repair of the injured mucosa, however, as seen in rats anesthetised with phenobarbital 180 minutes after ethanol was given, was similar in capsaicin and vehicle pretreated animals. Ablation of capsaicin sensitive afferent neurones was verified by a depletion of calcitonin gene related peptide from the gastric corpus wall. These findings indicate that nociceptive neurones control mechanisms of defence against acute injury but are not required for rapid repair of injured mucosa.     

Protective action of capsaicin and chilli on haemorrhagic shock-induced gastric mucosal injury in the rat

Chilli and its pungent ingredient, capsaicin, have been shown to protect against experimental gastric mucosal injury induced by various necrotizing agents such as ethanol and aspirin and stress. We investigated the effect of capsaicin and long-term ingestion of chilli on haemorrhagic shock-induced gastric mucosal injury in the rat. Anaesthetized male Sprague-Dawley rats were subjected to haemorrhagic shock by withdrawing blood to reduce the mean arterial blood pressure to 30–40 mmHg with subsequent reinfusion of shed blood. This resulted in gastric mucosal injury with readily identifiable haemorrhagic lesions. Capsaicin (5mg) administered prior to, but not after, haemorrhagic shock, significantly reduced the gastric mucosal injury in intact animals. Sensory ablation with capsaicin pretreatment (125 mg/kg bodyweight) abolished the gastroprotective effect afforded by capsaicin. Similarly, 4 week intake of chilli powder (360 mg daily) reduced the gastric mucosal injury in intact, but not in capsaicin-desensitized rats. Capsaicin and long-term chilli intake protected against haemorrhagic shock-induced gastric mucosal injury and the protection may be mediated by capsaicin-sensitive afferent neurons. Our studies are of potential significance in the context of stress ulcer disease in the human.     

Gastric hyperemia accompanying acid secretion is not mediated by sensory nerves

It is not known how the signal to increase gastric mucosal blood flow is passed from the gastric parietal cell layer to the resistance vessels in the submucosa. We tested the hypothesis that mucosal hyperemia accompanying stimulated gastric acid secretion is mediated by capsaicin-sensitive sensory nerves. Rats were denervated by systemic capsaicin treatment (125 mg/kg, subcutaneously, 10–14 days prior to experimentation). Acid secretion was stimulated by intravenous pentagastrin (4, 12, and 36 μg/kg/hr) and was measured by a continuous perfusion method. Mucosal blood flow was measured by the hydrogen gas clearance method. Sensory denervation did not affect basal blood pressure, gastric acid secretion, or mucosal blood flow. In control rats, increases in gastric mucosal blood flow and acid secretion were dose-related. With denervation, not only was there no inhibition of the blood flow response to acid secretion, but the dose-dependent rise in acid secretion was accompanied by increased mucosal blood flow that was out of proportion to the acid secretory response. The capsaicin-sensitive afferent fibers do not transmit the signal to increase gastric mucosal blood flow in response to stimulated acid secretion. It appears that sensory nerves modulate but do not mediate the mucosal hyperemic response to acid secretion.     

Intragastric Capsaicin Stimulates Motility of Upper Gut and Proximal Colon via Distinct Pathways in Conscious Dogs

The aim of the present study was to investigatethe effect and mechanism of action of intragastric andintraduodenal capsaicin on gastrointestinal motility.Five mongrel dogs were equipped with eight strain gauge force transducers on the stomach, smallintestine, and proximal colon. In the interdigestivestate, capsaicin was administered into the gastric orduodenal lumen. The effects of atropine, hexamethonium, ondansetron, and FK888 on capsaicin-inducedcontractions were studied. Intragastric capsaicininduced contractions within 15 min in the gastricantrum, duodenum, proximal jejunum, and proximal colon.These stimulatory effects were inhibited by atropineat all sites; by hexamethonium in the small intestineand colon; by ondansetron in the antrum, duodenum, andcolon; and by FK888 in the antrum and colon,respectively. Intraduodenal capsaicin had no effect oncontractility. Stimulation of afferent fibers bycapsaicin in the stomach but not in the duodenumaugments contractile activity in local and distantregions of the gut via distinct pathways.     

Gastric mucosal protection against ulcerogenic factors in the rat mediated by capsaicin-sensitive afferent neurons

Treatment of newborn rats with capsaicin (0.16 mmol/kg) is known to cause a permanent degeneration of certain, primarily unmyelinated, afferent neurons. In this study, experimentally induced gastric ulceration was investigated in adult rats treated with capsaicin as neonates. It was found that in capsaicin-treated animals the formation of gastric mucosal lesions in response to indomethacin, ethanol, or cysteamine was significantly enhanced as compared with vehicle-treated controls. The duodenal ulceration caused by cysteamine was not altered after capsaicin treatment. In further experiments the possible pathways involved in the effect of capsaicin treatment on gastric mucosal protection were explored. It was found that the capacity of gastric tissue to release prostaglandins E2 and I2 was unchanged after capsaicin treatment. Atropine, hexamethonium, cimetidine, or terbutaline all reduced gastric ulceration in response to indomethacin in both solvent- and capsaicin-treated rats but did not counteract the enhancement of the ulcerogenic effect of indomethacin in capsaicin-treated rats. Guanethidine enhanced the ulcerogenic effect of indomethacin in solvent-treated but not in capsaicin-treated animals. Ethanol-induced formation of gastric lesions remained unaltered by guanethidine in both solvent- and capsaicin-treated rats. These results indicate that capsaicin-sensitive afferent neurons are involved in gastric mucosal protection against ulcerogenic factors. The data further suggest that this type of gastric defense is primarily due to a local mechanism initiated by sensory nerve endings in the gastric mucosa.     

Influence of Capsaicin-Sensitive Afferent Fibers on Acetic Acid-Induced Chronic Gastric Ulcers in Rats

Tramontana M. Renzi D, Calabró A. Panerai C. Milani S, Surrenti C, Evangelista S. Influence of capsaicin-sensitive afferent fibers on acetic acid-induced chronic gastric ulcers in rats. Scand J Gastroenterol 1994;29:406-413.

Accumulating evidence indicates that capsaicin-sensitive afferent fibers play a pivotal role in acute gastroprotection. However, whether they also influence healing of chronic gastric ulcers is still unknown. The effects of ablation of sensory neurons on acetic acid-induced chronic gastric ulcers in rats were investigated at morphologic and biochemical levels by computerized imaging analysis of the ulcerated area, histologic examination, and neuropeptide determination. Afferent nerve ablation, as a result of treating rats with a neurotoxic dose of capsaicin (50 + 50 mg/kg subcutaneously over 2 days), produced a significant increase in the ulcer area at 1 and 2 weeks after acetic acid injection. The delay in ulcer healing was associated with a marked and persistent decrease in tissue calcitonin gene-related peptide-like immunoreactivity. whereas gastric vasoactive intestinal polypeptide was unaffected by capsaicin pretreatment. Histologically, as compared with control rats, capsaicin-desensitized animals only differed in a slight increase in the inflammatory infiltrate during the early phase of ulcer formation. These findings suggest that capsaicin-sensitive afferent fibers may play a role in the healing of chronic experimental gastric ulcers in rats, but the underlying mechanisms remain to be elucidated and deserve further investigation.     

Beneficial effect of a novel pentadecapeptide BPC 157 on gastric lesions induced by restraint stress,ethanol, indomethacin,and capsaicin neurotoxicity

Very recently, the integrity of capsaicin somatosensory neurons and their protection were suggested to be related to the activity in nociception of a newly discovered 15-amino acid peptide, BPC 157, shown to have strong beneficial effect on intestinal and liver lesions. Therefore, from this viewpoint, we have studied the gastroprotective effect of the pentadecapeptide BPC 157, on gastric lesions produced in rats by 96% ethanol, restraint stress, and indomethacin. The possible involvement of sensory neurons in the salutary actions of BPC 157 (10µg/kg, 10 ng/kg intraperitoneally) was studied with capsaicin, which has differential effects on sensory neurons: a high dose in adult (125 mg/kg subcutaneously, 3 months old) or administration (50 mg/kg subcutaneously) to neonatal animals (age of the 7 days) destroys sensory fibers, whereas a low dose (500µg/kg intraperitoneally) activates neurotransmitter release and protective effects on the mucosa. In the absence of capsaicin, BPC 157 protected gastric mucosa against ethanol, restraint, and indomethacin application. In the presence of neurotoxic doses of capsaicin, the negative influence of capsaicin on restraint, ethanol, or indomethacin lesions consistently affected salutary activity of BPC 157. However, BPC 157 protection was still evident in the capsaicin-treated rats (either treated as adults or as newborns) in all of these assays. Interestingly, after neonatal capsaicin treatment, a complete abolition of BPC gastroprotection was noted if BPC 157 was applied as a single nanogram-regimen, but the mucosal protection was fully reversed when the same dose was used daily. In line with the excitatory dose of capsaicin the beneficial effectiveness of BPC 157 appears to be increased as well. Taken together, these data provide evidence for complex synergistic interaction between the beneficial effectiveness of BPC 157 and peptidergic sensory afferent neuron activity.     

Four response stages of capsaicin-sensitive primary afferent neurons to capsaicin and its analog: Gastric acid secretion, gastric mucosal damage and protection

Capsaicin is the active component of red hot peppers, which modifies specifically the capsaicin-sensitive sensory afferent nerves. The action of capsaicin is an initial short-lasting stimulation, which is followed by desensitization to capsaicin itself, and to other stimuli of afferent sensory nerves. Four response stages of capsaicin-sensitive primary afferents exist to capsaicin, depending on the dose and duration of exposure to the drug. These are excitation, a sensory blocking effect, long-term selective neurotoxic impairment, and irreversible cell destruction. The possible roles of four stages of capsaicin-sensitive primary afferents can be evaluated in relation to gastric acid secretion, and to the details of the defensive side of gastric mucosa against different chemicals, physical agents, drugs and other pathological stress. Capsaicin inhibited the gastric acid secretion in pylorus-ligated rats when it was given intragastrically at a dose of 0.4-1.8 microg/kg. Small doses of capsaicin (up to 800 microg, i.g.) produced a dose-dependent inhibition (ID50 = 400 microg), and its inhibitory effect was exerted for 1 h in healthy human subjects. While a small dose (5 microg/kg) of capsaicin caused inhibition, a high dose (50-100 mg/kg) enhanced the gastric mucosal lesions productivity by causing hyperacidity in pylorus-ligated animals. Capsaicin and its analog inhibited the development of different chemically induced gastric mucosal damage in various experimental models if they were given intragastric doses (microg/kg). The final effects of capsaicin depend on the dosage and timing. The different effects are excitation, a sensory-blocking effect, long-term selective neurotoxic impairment and irreversible cell destruction.