Capsaicin-sensitive Vagal Afferent Fibers Research Articles

The gastroprotective effect of obestatin on indomethacin-induced acute ulcer is mediated by a vagovagal mechanism.

In order to investigate the role of the vagus nerve in the possible gastroprotective effect of obestatin on the indomethacin-induced acute oxidative gastric injury, Sprague-Dawley rats of both sexes were injected subcutaneously with indomethacin (25 mg/kg, 5% NaHCO3) followed by obestatin (10, 30 or 100 μg/kg). In other sets of rats, surgical vagotomy (Vx) or selective degeneration of vagal afferent fibers by perivagal capsaicin was performed before the injections of indomethacin or indomethacin + obestatin (30 μg/kg). Gastric serosal blood flow was measured, and 4 h after ulcer induction gastric tissue samples were taken for histological and biochemical assays. Obestatin reduced the severity of indomethacin-induced acute ulcer via the reversal of reactive hyperemia, by inhibiting ulcer-induced neutrophil infiltration and lipid peroxidation along with the replenishment of glutathione (GSH) stores, whereas Vx abolished the inhibitory effect of obestatin on blood flow and lipid peroxidation, and worsened the severity of ulcer. On the other hand, serosal blood flow was even amplified by the selective denervation of the capsaicin-sensitive vagal afferent fibers, but obestatin-induced reduction in ulcer severity was not altered. In conclusion, the gastroprotective effect of obestatin on indomethacin-induced ulcer appears to involve the activation of the vagovagal pathway.

Learned flavor preferences induced by intragastric administration of rewarding nutrients: role of capsaicin-sensitive vagal afferent fibers

Learned flavor preferences can be established after intragastric nutrient administration by two different behavioral procedures, concurrent and sequential. In a concurrent procedure, two flavored stimuli are offered separately but at the same time on a daily basis: one stimulus is paired with the simultaneous intragastric administration of partially digested food and the other with physiological saline. In sequential learning, the two stimuli are presented during alternate sessions. Neural mechanisms underlying these learning modalities have yet to be fully elucidated. The aim of this study was to examine the role of vagal afferent fibers in the visceral processing of rewarding nutrients during concurrent (experiment 1) and sequential (experiment 2) flavor preference learning in Wistar rats. For this purpose, capsaicin, a neurotoxin that destroys slightly myelinated or unmyelinated sensory axons, was applied to the subdiaphragmatic region of the esophagus to selectively damage most of the vagal afferent pathways that originate in the gastrointestinal system. Results showed that capsaicin [1 mg of capsaicin dissolved in 1 ml of vehicle (10% Tween 80 in oil)] blocked acquisition of concurrent but not sequential flavor preference learning. These results are interpreted in terms of a dual neurobiological system involved in processing the rewarding effects of intragastrically administered nutrients. The vagus nerve, specifically capsaicin-sensitive vagal afferent fibers, would only be essential in concurrent flavor preference learning, which requires rapid processing of visceral information.

Capsaicin-sensitive afferent vagal fibers are involved in concurrent taste aversion learning

Taste aversion learning (TAL) is a type of learning characterized by rejection of a gustatory/flavor stimulus as a consequence of its pairing with visceral discomfort and malaise. TAL can be established in the laboratory by two different behavioral procedures, concurrent or sequential. Neural mechanisms of these learning modalities remain to be elucidated, but several studies have discussed the implication of various anatomical structures, including the vagus nerve. The aim of this study was to examine the role of capsaicin-sensitive vagal afferent fibers in concurrent (Experiment 1) and sequential (Experiment 2) TAL in Wistar rats. Results showed that perivagal administration of capsaicin (1 mg of capsaicin dissolved in 1 ml of vehicle (10% Tween 80 in oil)) blocked acquisition of concurrent but not sequential TAL. These data support the hypothesis of two different modalities of TAL mediated by distinct neurobiological systems, with vagal nerve participation only being essential in concurrent TAL.

Vagal afferent is involved in short-pulse gastric electrical stimulation in rats.

This study investigated the effect of gastric electrical stimulation (GES) on vagal activity and its possible vagal afferent-mediated mechanisms. Sixty rats implanted with gastric serosal electrodes were divided into six groups (control, vehicle, local capsaicin, perivagal capsaicin, systemic capsaicin, and vagotomy). GES with six sets of parameters was performed in the control group; and GES with one set of effective parameters was performed in the other five groups. Spectral analysis of heart rate variability was used to assess vagal activity. Regular gastric slow waves were recorded in the control rats with a frequency of 4.8 cycles/min. Vagotomy significantly reduced the frequency of the gastric slow wave but did not induce dysrhythmia. Capsaicin did not alter the gastric slow wave. Short-pulse (300-microsec) GES significantly increased vagal activity at a frequency four times the intrinsic slow-wave frequency. Stimulation at a lower frequency or with a long pulse (300 msec) had no effect on vagal activity. Vagotomy or capsaicin administered perivagally, systemically, or locally abolished the effect of GES on the vagal activity. GES with short but not long pulses is capable of altering vagal activity. This effect is mediated by capsaicin-sensitive vagal afferent fibers.

Anti-inflammatory effects of leptin and cholecystokinin on acetic acid-induced colitis in rats: role of capsaicin-sensitive vagal afferent fibers

Leptin and cholecystokinin (CCK) have a synergistic interaction in the suppression of food intake, and afford similar gastroprotective activity. The present study was designed to investigate the putative protective effects of CCK and leptin on acute colonic inflammation. Leptin or CCK-8s was injected to rats intraperitoneally immediately before and 6 h after the induction of colitis with acetic acid. CCK-A receptor antagonist (L-364,718) or CCK-B receptor antagonist (L-365,260) was injected intraperitoneally 15 min before leptin or CCK treatments. In a group of rats, vagal afferent fibers were denervated by topical application of capsaicin on the cervical vagi. Rats were decapitated at 24 h, and the distal 8 cm of the colon were removed for macroscopic scoring, determination of tissue wet weight index (WWI), histologic assessment and tissue myeloperoxidase (MPO) activity. All inflammation parameters were increased by acetic acid-induced colitis compared to control group. Leptin or CCK-8s treatment reduced these parameters in a similar manner, while co-administration of leptin and CCK was found to be more effective in reducing the macroscopic score and WWI. CCK-8s-induced reduction in the score and WWI was prevented by CCK-A, but not by CCK-B receptor antagonist, whereas neither antagonist altered the inhibitory effect of leptin on colitis-induced injury. On the other hand, perivagal capsaicin prevented the protective effects of both CCK-8s and leptin on colitis. Our results indicate that leptin and CCK have anti-inflammatory effects on acetic acid-induced colitis in rats, which appear to be mediated by capsaicin-sensitive vagal afferent fibers involving the reduction in colonic neutrophil infiltration.

Leptin and CCK have a synergistic anti-inflammatory effect on acetic acid-induced colitis in rats: Role of capsaicin-sensitive vagal afferent fibers

caused an increase m colonic IL-10 level. Furthermore, corresponding modulation in colonic fNF-a and IL-10 mRNA expressions by mtracolonic AS and heparin had also been demonstraled. Alternately, oral AS and heparin did not exhibit a strong and coherent effect in regulating the proniilantmatory mediators and cytokines in the colon. Conclusion: The orthodox drug heparin and extract from the traditional Chinese medicine danggui could act in concert to establish art effi~ctive therapeutic regimen to treat colitis diseases via immunomodulation of cytokines and the msuhnig regulation of proinflammatory mediators.

Endogenous CCK disrupts the MMC pattern via capsaicin-sensitive vagal afferent fibers in the rat.

A meal disrupts migrating motor complexes (MMC) in the rat intestine through stimulation of peripheral cholecystokinin (CCK)-B and central CCK-A receptors. The aim of this study was to determine pathways implicated in postprandial disruption of the MMC mediated by CCK. Sprague-Dawley rats were prepared with electrodes for electromyography in the small intestine, and ablation of vagal afferent C-fibers by capsaicin was carried out. Endogenous release of CCK was induced by oral administration of soybean trypsin inhibitor (SBTI). In control rats SBTI disrupted MMC and generated an irregular spiking activity that lasted longer than 3 h. Intravenous infusion of L-365,260 (2 x 10(-7) mol/kg) but not of L-364,718 (3 x 10(-9) mol/kg) restored the MMC pattern. In capsaicin-treated rats, SBTI did not modify fasting activity. Infusion of CCK octapeptide (CCK-8) at 3 x 10(-9) mol.kg-1.h-1 disrupted the MMC, although the response was quantitatively and qualitatively different from SBTI. The effect was reversed by intravenous infusion of L-364,718 or L-365,260 and intracerebroventricular infusion of L-364,718. In capsaicin-treated rats, the intracerebroventricular or intravenous infusion of L-364,718 inhibited CCK-8 effects. However, the intravenous infusion of L-365,260 did not reverse the MMC pattern. These results suggest that the disruption of the MMC mediated by CCK is due to stimulation of peripheral CCK-B receptors located in vagal afferent fibers. This initiates a reflex including stimulation of central CCK-A receptors. Exogenous CCK also stimulates peripheral CCK-A receptors not located in capsaicin-sensitive vagal afferent fibers.

Capsaicin‐Sensitive Vagal Afferent Fibers and Gastric Motility: Evidence for an “Axon Reflex” Mechanism

The role of capsaicin‐sensitive afferent fibers in gastric motility has been studied in normal rats and in rats treated at birth with the sensory neurotoxin capsaicin, a procedure known to destroy up to 90% of unmyelinated afferent fibers. Gastric motility was measured as intragastric pressure changes evoked by the distention of the stomach with 8 to 10 ml of normal (154 mM) or 1 M saline solution. No differences were observed between the motility patterns evoked by gastric distention with these two solutions. Distention of the stomach evoked a significantly lower basal tone and a reduced number and amplitude of phasic contractions in capsaicin‐treated rats compared to control rats. Intravenous administration of the ganglionic blocker hexamethonium substantially reduced phasic motility in both groups of animals. Subsequent bilateral vagotomy had little extra effect. After bilateral vagotomy, electrical stimulation at supramaximal intensities of the peripheral end of the cut right vagus in the presence of hexamethonium produced an inhibition of the gastric basal tone in both groups of rats and, on cessation of stimulation, a series of rebound contractions in most control animals, but not in those treated at birth with capsaicin. These results provide evidence for an efferent role of vagal afferent fibers in the control of gastric motility, possibly via an axon reflex mechanism.

Capsaicin-sensitive afferent fibers contribute to gastric mucosal blood flow response to electrical vagal stimulation

Electrical stimulation of the peripheral vagus produces a noncholinergic increase in gastric mucosal blood flow (GMBF) via unknown mechanisms. The purpose of this study was 1) to investigate whether a portion of the increase in GMBF during prolonged electrical vagal stimulation involves a mechanism separate from augmented acid secretion and 2) to determine whether antidromic activation of afferent fibers contributes to the vascular or secretory responses to electrical vagal stimulation. Electrical vagal stimulation (40 V, 6 Hz, 2 ms) applied for 30 min to the distal cut end of the subdiaphragmatic ventral vagus significantly increased gastric acid secretion and GMBF measured by hydrogen gas clearance. Atropine (0.15 mg/kg iv) or omeprazole (10 mumol/kg iv) completely abolished the secretory response to electrical vagal stimulation, while a significant increase in GMBF remained. Pretreatment with perineural application of the sensory neurotoxin capsaicin to both cervical vagi significantly reduced by 48% the increase in GMBF but not gastric acid secretion; atropine completely abolished the remaining vascular response in capsaicin-treated rats. These results suggest that prolonged electrical vagal stimulation induces a sustained increase in GMBF partially independent of augmented acid secretion and that the noncholinergic portion of the vascular response is mediated by capsaicin-sensitive vagal afferent fibers.

Capsaicin-sensitive vagal afferent fibers do not contribute to histamine H 2 receptor agonist-induced gastric acid secretion in anesthetized rats

The effect of perivagal capsaicin treatment on gastric acid secretion induced by the histamine H 2 receptor agonist, dimaprit dihydrochloride, and the effect of the histamine H 1 receptor agonist, 2-thiazolylethylamine dihydrochloride, on gastric acid secretion were studied in acute gastric fistula rats anesthetized with urethane. The integrated secretory response for the 2 h following subcutaneous (s.c.) administration of dimaprit dihydrochloride (5–20 mg/kg) did not differ in capsaicin- compared to vehicle-treated rats. Administration of 2-thiazolylethylamine dihydrochloride (20 mg/kg s.c.) did not modify gastric acid secretion in untreated rats. The present study demonstrates that the previously reported reduction in the secretory response to histamine by perivagal capsaicin treatment is unrelated to histamine H 1 or H 2 receptor.

Capsaicin-sensitive vagal afferents contribute to gastric acid and vascular responses to intracisternal TRH analog

Central injection of TRH or its stable analog, RX77368, produces a vagal cholinergic stimulation of gastric acid secretion, mucosal blood flow and motor function. In the present study, we have investigated the contribution of capsaicin-sensitive vagal afferent fibers to the gastric responses to intracisternal injection of RX77368. Gastric acid secretion, measured in acute gastric fistula rats anesthetized with urethane,in response to intracisternal injection of RX77368 (3–30 ng) was reduced by 21–65% by perineural pretreatment of the vagus nerves with capsaicin 10–20 days before experiments. The increase in gastric mucosal blood flow measured by hydrogen gas clearance induced by intracisternal injection of RX77368 (30 ng) was also reduced by 65% in capsaicin-pretreated rats. In contrast, increases in gastric motor function measured manometrically or release of gastric luminal serotonin in response to intracisternal injection of RX77368 (3–30 ng) were unaltered by capsaicin pretreatment. The mechanism by which vagal afferent fibers contribute to the secretory and blood flow responses to the stable TRH analog is unclear at present, but it is possible that the decrease in gastric mucosal blood flow by lesion of capsaicin-sensitive vagal afferents limits the secretory response.

Capsaicin-sensitive vagal afferent fibers and stimulation of gastric acid secretion in anesthetized rats

The sensory neurotoxin, capsaicin, has been used to study the reflex pathway by which gastric acid secretion increases in response to gastric distension in urethane-anesthetized rats. Capsaicin (1%) or vehicle (10% Tween 80 in olive oil) was applied directly to each cervical vagus 7–14 days prior to experiments. Gastric acid secretion was measured in acute gastric fistula rats by continuous intragastric perfusion and back titration or by flushing the gastric contents with saline every 10 min. Gastric acid secretion was stimulated by distension (5 ml for 6 min) or by injection of secretagogues (histamine 5.0 mg/kg s.c., bethanchol 0.5 mg/kg s.c. or pentagastrin 16 μg/kg per h i.v.). Gastric distension increased gastric acid secretion 6.2 times over basal gastric acid secretion in vehicle-treated control rats; capsaicin pretreatment significantly reduced this response by 40%. Bilateral cervical vagotomy significantly reduced the secretory response to gastric distension in the vehicle-treated group to a level not significantly different from capsaicin-treated rats. The secretory response to histamine was reduced by 42% in capsaicin-treated rats compared to vehicle pretreatment whereas the responses to pentagastrin and bethanechol were unaltered. These results indicate that capsaicin-sensitive vagal afferent fibers eediate the vagal portion of the secretory response to gastric distention; in addition these afferents play a role in the gastric acid secretory response to histamine