M.J. Fargeas

Central action of interleukin 1β on intestinal motility in rats: Mediation by two mechanisms

BACKGROUND Interleukin 1 (IL-1) can influence gut functions by inhibiting gastric acid secretion. This study was performed to investigate the effects of IL-1 on intestinal motility and the mechanisms involved. METHODS The effects of IL-1 beta were determined by electromyography in conscious rats with implanted electrodes and a permanent catheter in a lateral brain ventricle. RESULTS Intracerebroventricular IL-1 beta (15 ng) administered to fed rats immediately stimulated cecocolonic spike bursts and caused a migrating myoelectric complex pattern after a delay in the small intestine. Tenfold higher doses of peripherally administered IL-1 beta did not promote similar reactions. The IL-1 antagonist reduced the small intestinal effect of IL-1 beta and blocked the cecocolonic stimulation. Indomethacin and SC 19220 reduced the small intestinal effects but did not antagonize the increase in cecocolonic contractions. In contrast, alpha-helical CRF9-41 blocked the increase of cecocolonic contractions but did not antagonize the IL-1 beta-induced effects on the small intestine. CONCLUSION IL-1 betas effects on intestinal motility can be mainly ascribed to a central action. The cecocolonic stimulation may be mediated by brain corticotropin-releasing factor, whereas the small intestinal effects involve a prostaglandin mediation.

c-fos expression in specific rat brain nuclei after intestinal anaphylaxis : involvement of 5-HT3 receptors and vagal afferent fibers

The c-fos immediate-early gene is acutely induced in brain after various stimuli from the digestive tract. 5-HT3 receptors and vagal afferents have been found involved in intestinal motor disturbances induced by intestinal anaphylaxis. Our aim was to determine whether intestinal anaphylaxis activates brain structures, using c-fos expression, and to evaluate the modulation of c-fos induction by 5-HT3 receptors and vagal afferents. The effects of antigen challenge on intestinal motility were evaluated in ovalbumin-sensitized Hooded Lister rats chronically fitted with NiCr electrodes in the jejunal wall. Intestinal motility was assessed in conscious rats pretreated or not by perivagal capsaicin or a 5-HT3 antagonist (ondansetron). In sensitized rats, ovalbumin disrupted for 62.4 +/- 9.5 min the jejunal migrating motor complexes (MMC) and an important c-fos expression was detected in the nucleus tractus solitarius (NTS), lateral parabrachial nucleus (LPB) and paraventricular nucleus of the hypothalamus (PVN). Intraperitoneal administration of ondansetron or perivagal capsaicin treatment significantly reduced the duration of MMC disruption and attenuated markedly c-fos staining in the 3 brain sites. In contrast, intracerebroventricular administration of ondansetron significantly reduced jejunal motor alterations but did not diminish the c-fos expression, suggesting a role of central 5-HT3 receptors in the efferent control of the intestinal disturbances. Blockade of both c-fos expression and MMC disruption by systemic ondansetron and by perivagal capsaicin indicates that some brainstem nuclei are involved in digestive disturbances after intestinal anaphylaxis, and reflects an involvement of peripheral 5-HT3 receptors on vagal afferents. The reduction of c-fos staining in NTS as well as in LPB and PVN after perivagal capsaicin suggests that the NTS is the primary relay in the activation of the central nervous system during intestinal allergic challenge.

Central control of intestinal motility by prostaglandins: A mediator of the actions of several peptides in rats and dogs

The effect of intracerebroventricular and intravenous administrations of prostaglandin E2 on gastrointestinal motility were investigated in conscious rats and dogs using electrodes and strain gauges, respectively. Injections were performed during the fed state and the motor changes were compared with those after intracerebroventricular administration of calcitonin, neurotensin, and (D-Ala2, Met5) enkephalinamide. Intracerebroventricular administration of prostaglandin E2 (0.5 micrograms) to fed rats restored the migrating myoelectric complex for 67 +/- 16 min. A migrating myoelectric complex-restoring effect was also observed after intracerebroventricular administration of calcitonin (0.02 U) and neurotensin (80 ng). This effect was blocked by previous intracerebroventricular administration of indomethacin (0.25 mg). Administered centrally to dogs but not intravenously at a 10-fold greater dose, prostaglandin E2 (0.1 microgram/kg) reduced (52.8%) the duration of the jejunal postprandial motor state similarly to that observed after intracerebroventricular administration of calcitonin (0.1 U/kg), neurotensin (0.1 microgram/kg), and (D-Ala2, Met5) enkephalinamide (0.1 microgram/kg). These effects of calcitonin and neurotensin were abolished 4 h after an intramuscular injection of indomethacin (2 mg/kg), whereas those of (D-Ala2, Met5) enkephalinamide persisted. These results suggest that (a) prostaglandins act centrally to control the pattern of intestinal motility in both rats and dogs and (b) calcitonin and neurotensin when injected intracerebroventricularly affect the intestinal motor profile probably by stimulating prostaglandin release within the brain.

Central α2-adrenergic control of the pattern of small intestinal motility in rats

Abstract The effects of central and peripheral administration of α 2 -adrenoceptor agonists and antagonists on small intestinal motility were examined in conscious rats chronically fitted with electrodes implanted in the duodenojejunal wall and a cannula placed in a cerebral lateral ventricle. In fasted rats, intracerebroventricular or intraperitoneal administration of clonidine (5 μg) immediately disrupted the migrating myoelectric complex pattern with a total inhibition of spiking activity during the first hour, followed by a period of irregular spiking activity for 2 h. The inhibition was abolished by previous intramuscular administration of yohimbine (600 μg), and the period of irregular activity was suppressed by intracerebroventricular yohimbine (30 μg). Naphazoline, an α 2 -agonist that poorly crosses the blood-brain barrier, only inhibited spiking activity when administered intraperitoneally (1 μg) and induced only a period of irregular spiking activity when administered intracerebroventricularly at the same dose. In fed rats, intracerebroventricular administration of yohimbine or phentolamine (30 μg), and to a lesser extent prazosin, restores a migrating myoelectric complex pattern typical of the fasted state. Peripheral administration of these three antagonists at a dose 20 times higher was ineffective. Finally, both feeding and central administration of α 2 -agonists disrupt the migrating myoelectric complex pattern. Such pharmacologic data suggest a possible role of central α 2 -adrenoceptors in the regulation of intestinal motility in rats.

Calcitonin gene-related peptide: brain and spinal action on intestinal motility.

The effects of intracerebroventricular (ICV) and intrathecal (IT) administration of calcitonin gene-related peptide (CGRP) on intestinal motility were examined in conscious rats chronically fitted with intraparietal electrodes in the duodeno-jejunum and a cannula in a cerebral lateral ventricle or catheter in the subarachnoid space. ICV administration of CGRP (0.5-10 micrograms) restores the fasted pattern of intestinal motility in fed rats in a dose-related manner. Intrathecal administration of CGRP or calcitonin also induces fasted pattern but after a 30 min delay. These effects persisted after transection of the spinal cord and no change in intestinal motility appeared after intravenous administration of CGRP at a dose effective when given IT. This study suggests that CGRP, as calcitonin, has a neuromodulatory role in the control of intestinal motility at both brain and spinal cord levels.

Boosted systemic immune and local responsiveness after intestinal inflammation in orally sensitized guinea pigs

BACKGROUND & AIMS Intestinal inflammation resulting in disruption of the mucosal barrier function has been proposed as a cause of increased incidence of allergic diseases. This study was designed to evaluate whether intestinal inflammation is able to change the immune responsiveness to sensitization and antigen challenge responses. METHODS Guinea pigs orally sensitized to cows milk proteins were either treated or not treated with trinitrobenzenesulfonic acid (TNBS) to induce intestinal inflammation and compared with control animals (not sensitized). Systemic immune and local responsiveness to antigen challenge were assessed by measuring antibody serum titers, colonic fluid secretion, mucosal histamine level, and mucus depletion. Intestinal permeability was evaluated from 51Cr-ethylenediaminetetraacetic acid (EDTA) recovery and beta-lactoglobulin serum level. RESULTS Immunoglobulin E titers were higher in TNBS-treated animals than in non-TNBS-treated sensitized animals. Antigen challenge in TNBS-treated animals induced a fourfold increase of colonic secretion and greater histamine and mucus depletion than in non-TNBS-treated animals. Permeability to 51Cr-EDTA increased 5 days after TNBS treatment but was unchanged after antigen challenge. In contrast to controls, beta-lactoglobulin was not detected in the sera of challenged sensitized and TNBS-treated animals. CONCLUSIONS Intestinal inflammation increasing gut permeability enhances the sensitization process. Therefore, local anaphylactic reactions are exacerbated after antigen challenge.

The involvement of opiate receptors in the effects of trimebutine on intestinal motility in the conscious dog.

The effects of intravenous (i.v.) vs intracerebroventricular (i.c.v.) administration of trimebutine on the motility of the small intestine and colon of fasted dogs were assessed using chronic electromyography. Trimebutine, injected intravenously, stimulated small intestinal motility, by inducing a propagated phase of regular spike activity, and inhibited colonic motility for some 4 h. These effects were not reproduced by i.c.v. administration which disrupted the cyclic motor profile of the small intestine for about 2·5 h and did not modify colonic motility. The stimulation of the small intestine motility induced by i.v. administration of the drug was blocked by previous i.v. but not by i.c.v. administration of naloxone. It was concluded that in the dog, the effects of trimebutine on the small intestine but not on the colon, involve peripheral opiate receptors.

Involvement of Capsaicin-Sensitive Afferent Nerves in the Intestinal Motor Alterations Induced by Intestinal Anaphylaxis in Rats

Alteration of intestinal myoelectrical activity is a characteristic feature of food protein-induced intestinal anaphylaxis in the conscious rat. The motility changes induced by antigen challenge were appraised in egg-albumin-sensitized rats, chronically implanted with NiCr electrodes in the duodenojejunal wall. Intraduodenal infusion of egg albumin given to fasted sensitized rats triggered a disruption of the cyclic pattern of small intestinal motility lasting 79.1 +/- 23.3 min. The duration of the challenge effect on intestinal myoelectrical activity was significantly reduced by systemic capsaicin pretreatment (125 mg/kg) but to a lesser extent by perivagal capsaicin. Substance P (SP) antagonists (SP 4-11 and CP 96.345) and atropine were also able to shorten the duration of the antigen-challenge-induced alteration of intestinal motility. It is concluded that SP and capsaicin-sensitive afferent nerve endings play an important role in the intestinal anaphylaxis-induced disturbances of intestinal motility.

Action of t-2 toxin on gastrointestinal transit in mice: Protective effect of an argillaceous compound

Using sodium [51Cr]chromate as radiolabeled marker, gastrointestinal transit of a milk test meal was determined in mice receiving for 4 days T-2 toxin (1 mg/kg per day per os) alone or with a clay, smectite (2 g/kg per day), given according to four different procedures. Gastric emptying and small intestinal transit were significantly accelerated after the 1st T-2 administration and during the 4 days of treatment. When smectite was given together with the toxin with or without pretreatment by smectite alone for 2 days, the T-2 induced disturbances in gastrointestinal transit remained unchanged. A pretreatment by smectite for 4 days abolished the T-2 induced acceleration of gastric emptying but not of small intestinal transit. When T-2 was incubated with smectite for 24 h before oral administration, gastric emptying and small intestinal transit were not significantly accelerated.

Central actions of calcitonin on body temperature and intestinal motility in rats: evidence for different mediations.

The effects of intracerebroventricular (i.c.v.) administration of calcitonin and PGE2 on intestinal motility and body temperature were examined in conscious rats chronically fitted with intraparietal electrodes in the small intestine, a cannula in a cerebral lateral ventricle and a subcutaneous thermistor probe. Both calcitonin and PGE2 restored the fasted pattern of intestinal motility in fed rats and induced an increase in body temperature. Indomethacin, an inhibitor of the cyclooxygenase with calcium antagonistic properties, and TMB-8, an intracellular calcium antagonist, blocked the effects of calcitonin on intestinal motility and body temperature. Piroxicam, an inhibitor of the cyclooxygenase which does not affect calcium uptake blocked the thermic but not the intestinal effects of calcitonin. TMB-8 but not indomethacin or piroxicam partially blocked the effects of PGE2 on both intestinal motility and body temperature. It is concluded that the central hyperthermic effect of calcitonin is mediated through the formation and the release of prostaglandins whereas the central action of calcitonin on digestive motility results from intracerebral effects on calcium fluxes.