Biomedical subjects

Hubert Mönnikes

Publications and source records attributed to Hubert Mönnikes.

At least 19 recordsLinked to original sources

PubMed2006

Peripheral injection of CCK-8S induces Fos expression in the dorsomedial hypothalamic nucleus in rats.

Peripheral cholecystokinin (CCK) plays a physiological role in the regulation of food intake. The dorsomedial hypothalamic nucleus (DMH) has been implicated in the brain regulation of food intake and satiety. The aim of this study was to determine if peripherally administered CCK affects neuronal activity in the DMH, as assessed by Fos expression. Density of Fos-positive neurons was determined in the DMH, paraventricular nucleus of the hypothalamus (PVN), arcuate nucleus of the hypothalamus (ARC) and ventromedial hypothalamic nucleus (VMH) in non-fasted Sprague-Dawley rats in response to intraperitoneally (ip) injection of CCK-8S (2 microg/kg, n=6) or vehicle (0.15 M NaCl; n=6). CCK-8S increased Fos immunoreactivity in the DMH (mean+/-SEM; cells/section: 108+/-10 versus 54+/-6, p<0.001) and PVN (120+/-12 versus 20+/-3, p<0.001) compared to the vehicle group while not influencing Fos expression in the ARC and VMH. Double labeling showed that 27.4+/-6.4% (n=3) of Fos-positive neurons induced by CCK-8S were positive for corticotropin-releasing factor immunoreactivity, that were mainly localized in the ventral part of the DMH, and encircled in a network of tyrosine-hydroxylase-immunoreactive positive fibers. These data indicate that in addition of the PVN, peripheral CCK increases neuronal activity in the DMH suggesting a possible role in this hypothalamic nucleus in the satiating effect of the peptide.

Adrenal Cortex Hormones↗

PubMed2006

Bombesin, but not amylin, blocks the orexigenic effect of peripheral ghrelin.

The interaction between ghrelin and bombesin or amylin administered intraperitoneally on food intake and brain neuronal activity was assessed by Fos-like immunoreactivity (FLI) in nonfasted rats. Ghrelin (13 microg/kg ip) increased food intake compared with the vehicle group when measured at 30 min (g/kg: 3.66 +/- 0.80 vs. 1.68 +/- 0.42, P < 0.0087). Bombesin (8 microg/kg) injected intraperitoneally with ghrelin (13 microg/kg) blocked the orexigenic effect of ghrelin (1.18 +/- 0.41 g/kg, P < 0.0002). Bombesin alone (4 and 8 microg/kg ip) exerted a dose-related nonsignificant reduction of food intake (g/kg: 1.08 +/- 0.44, P > 0.45 and 0.55 +/- 0.34, P > 0.16, respectively). By contrast, ghrelin-induced stimulation of food intake (g/kg: 3.96 +/- 0.56 g/kg vs. vehicle 0.82 +/- 0.59, P < 0.004) was not altered by amylin (1 and 5 microg/kg ip) (g/kg: 4.37 +/- 1.12, P > 0.69, and 3.01 +/- 0.78, respectively, P > 0.37). Ghrelin increased the number of FLI-positive neurons/section in the arcuate nucleus (ARC) compared with vehicle (median: 42 vs. 19, P < 0.008). Bombesin alone (4 and 8 microg/kg ip) did not induce FLI neurons in the paraventricular nucleus of the hypothalamus (PVN) and coadministered with ghrelin did not alter ghrelin-induced FLI in the ARC. However, bombesin (8 microg/kg) with ghrelin significantly increased neuronal activity in the PVN approximately threefold compared with vehicle and approximately 1.5-fold compared with the ghrelin group. Bombesin (8 microg/kg) with ghrelin injected intraperitoneally induced Fos expression in 22.4 +/- 0.8% of CRF-immunoreactive neurons in the PVN. These results suggest that peripheral bombesin, unlike amylin, inhibits peripheral ghrelin induced food intake and enhances activation of CRF neurons in the PVN.

Amyloid↗

PubMed2006

Functional abdominal pain syndrome.

Functional abdominal pain syndrome (FAPS) differs from the other functional bowel disorders; it is less common, symptoms largely are unrelated to food intake and defecation, and it has higher comorbidity with psychiatric disorders. The etiology and pathophysiology are incompletely understood. Because FAPS likely represents a heterogeneous group of disorders, peripheral neuropathic pain mechanisms, alterations in endogenous pain modulation systems, or both may be involved in any one patient. The diagnosis of FAPS is made on the basis of positive symptom criteria and a longstanding history of symptoms; in the absence of alarm symptoms, an extensive diagnostic evaluation is not required. Management is based on a therapeutic physician-patient relationship and empirical treatment algorithms using various classes of centrally acting drugs, including antidepressants and anticonvulsants. The choice, dose, and combination of drugs are influenced by psychiatric comorbidities. Psychological treatment options include psychotherapy, relaxation techniques, and hypnosis. Refractory FAPS patients may benefit from a multidisciplinary pain clinic approach.

Abdominal Pain↗

PubMed2006

Emotional stress reactivity in irritable bowel syndrome.

OBJECTIVES: Irritable bowel syndrome (IBS) has been proposed to be a stress-related disorder. Research on stress reactivity in IBS has yielded ambiguous results, regarding responses to physical and mental stress. This study aimed to investigate the responses to emotional stress in IBS patients. METHODS: Twelve IBS patients and 12 healthy individuals underwent public speaking anticipation as an emotional stressor and a control situation. Stress reactivity was quantified by subjective and psychophysiological measures. RESULTS: Stress responses were elicited in healthy controls and IBS patients. Differential stress responses were observed in measurements of heart rate. There was no change in rectal sensitivity under stress, whereas patients exhibited lower discomfort thresholds than healthy controls in all conditions. CONCLUSION: This study measured reactivity to an emotional stressor in IBS. It provides evidence that there is a specific alteration of stress responses in IBS patients, but no overall exaggerated stress response. IBS patients showed a broader and less specific response to emotional stress than healthy controls. Rectal sensitivity was unchanged under emotional stress both in IBS patients and healthy controls.

Adult↗

PubMed2006

The complete remission concept.

The presence of esophageal lesions and gastroesophageal reflux disease (GERD) symptoms do not coincide in some patients: some individuals suffer from the symptoms of GERD but have no evidence of GERD at endoscopy; while conversely, some with endoscopic evidence of GERD do not experience symptoms. In order to combine both healing of esophageal lesions and the presence of symptoms when measuring treatment efficacy, the concept of complete remission has been redefined to include both parameters. Until recently, an effective means of measuring GERD symptoms and response to therapy had been lacking. The symptomatic reflux questionnaire ReQuest(TM) was therefore developed; it is a validated, self-administered, hierarchical, dimension-oriented scale to assess response of a broad range of symptoms to treatment. It measures the frequency and intensity of seven symptom dimensions: acid complaints; upper abdominal complaints; lower abdominal complaints; nausea; sleep disturbances; other complaints; and general well-being (intensity only). ReQuest(TM) has recently been combined with an adaptation of the Los Angeles classification for endoscopic measurement of GERD, thus linking the assessment of symptom relief and healing of esophageal lesions. The new ReQuest(TM)/ LA-classification enables the detailed clinical characterization of GERD patients at any stage and accurate assessment of treatment outcome by a single global measure.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed2005

Impact of the intragastric location of extended release tablets on food interactions.

Gastrointestinal motility and transport as well as concomitant food intake are factors that are known to influence pharmacokinetics derived after intake of extended release dosage forms. However, the mechanisms behind these influencing factors are mostly unknown. In this study the gastrointestinal transit and the in vivo drug release of magnetically labelled extended release tablets containing felodipine were monitored together with the drug absorption phase of pharmacokinetics under fasting and fed conditions in six healthy volunteers using Magnetic Marker Monitoring. It was found that the in vivo drug release profiles of the tablets compared well under fasting and fed conditions. However, the plasma concentration profiles were strongly influenced by concomitant food intake. This could be attributed to elongated residence of the tablets in proximal parts of the stomach, resulting in delayed drug absorption and the occurrence of late high plasma peak concentrations. The lag time until the first appearance of felodipine in plasma and the residence time of the tablets in the proximal stomach, were found to be directly correlated. The study shows that increased plasma peak drug concentrations after intake of extended release formulations together with food can be explained by poor mixing in the proximal part of the stomach and are not necessarily due to failure of the formulation to control drug release (dose dumping).

Adult↗

PubMed2005

Megacolon in adulthood after surgical treatment of Hirschsprung's disease in early childhood.

Hirschsprung's disease (HD) is a disorder associated with congenital malformation of the enteric nervous system with segmental aganglionosis. Prevailing therapy includes a resection of the affected part of the bowel. However, patients often do not obtain complete functional improvement after surgical treatment. We present the case of a 25-year-old woman who had surgical treatment of HD in early childhood. After that procedure she had clinical features of constipation for years in the end, passing of stool once a week, requiring laxatives and enemas. We diagnosed an incomplete resection of the aganglionic bowel via rectal biopsy and resected the remaining aganglionic segment. Two months after surgery the patient's bowel function improved to a frequency of 1-4 stools per day. We conclude that regular follow-up is required to identify HD patients with persistent alterations of bowel function after surgery. In patients presenting with constipation, recognition of a remaining aganglionic segment or other alterations of the enteric nervous system should be aimed at in an early stage.

Adult↗

PubMed2005

Determination of ReQuest-based symptom thresholds to define symptom relief in GERD clinical studies.

BACKGROUND/AIMS: The growing importance of symptom assessment is evident from the numerous clinical studies on gastroesophageal reflux disease (GERD) assessing treatment-induced symptom relief. However, to date, the a priori selection of criteria defining symptom relief has been arbitrary. The present study was designed to prospectively identify GERD symptom thresholds for the broad spectrum of GERD-related symptoms assessed by the validated reflux questionnaire (ReQuest) and its subscales, ReQuest-GI (gastrointestinal symptoms) and ReQuest-WSO (general well-being, sleep disturbances, other complaints), in individuals without evidence of GERD. METHODS: In this 4-day evaluation in Germany, 385 individuals without evidence of GERD were included. On the first day, participants completed the ReQuest, the Gastrointestinal Symptom Rating Scale, and the Psychological General Well-Being scale. On the other days, participants filled in the ReQuest only. GERD symptom thresholds were calculated for ReQuest and its subscales, based on the respective 90th percentiles. RESULTS: GERD symptom thresholds were 3.37 for ReQuest, 0.95 for ReQuest-GI, and 2.46 for ReQuest-WSO. CONCLUSION: Even individuals without evidence of GERD may experience some mild symptoms that are commonly ascribed to GERD. GERD symptom thresholds derived in this study can be used to define the global symptom relief in patients with GERD.

Adult↗

PubMed2005

Novel measurement of rapid treatment success with ReQuest: first and sustained symptom relief as outcome parameters in patients with endoscopy-negative GERD receiving 20 mg pantoprazole or 20 mg esomeprazole.

BACKGROUND/AIMS: A prime concern for gastroesophageal reflux disease (GERD) patients is fast symptom control. Sparse valid information is available on the rapidity of the effect of proton pump inhibitors in provid ing symptom relief. The new reflux questionnaire ReQuest is validated for daily assessment of changes in GERD symptoms. Therefore, this study investigated the efficacy of 20 mg pantoprazole and 20 mg esomeprazole with regard to the time to symptom relief in patients with endoscopy-negative GERD (enGERD) using ReQuest. METHODS: 529 patients were treated with pantoprazole or esomeprazole over 4 weeks. ReQuest symptom scores were assessed daily. The mean and median times to first and sustained symptom relief were determined. RESULTS: Median time to first symptom relief was 2 days for both drugs (intention-to-treat population). The median time to sustained symptom relief was 3 days shorter with pantoprazole (10.0 vs. 13.0 days). The Hodges-Lehmann estimator for the difference in time to reach first and sustained symptom relief between both groups was 0.00 days. For both variables the one-sided 95% CI (Moses) was [0.00; infinity] documenting no significant differences between the treatment groups. CONCLUSIONS: The rapidity of symptom control can be evaluated by clinically significant parameters using ReQuest. Pantoprazole and esomeprazole are equally effective in the time to first and sustained symptom relief.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed2005

Magnetic Marker Monitoring: An application of biomagnetic measurement instrumentation and principles for the determination of the gastrointestinal behavior of magnetically marked solid dosage forms.

Magnetic Marker Monitoring offers an alternative to investigate the behavior of solid dosage forms in the organs of the gastrointestinal tract without the need to apply radiation. For Magnetic Marker Monitoring, the dosage form is marked as a permanent magnetic dipole by the incorporation of small amounts of ferromagnetic material, as for example the colorant black iron oxide, and subsequent magnetization. Thereby, the dosage form is labeled as the source of a well defined magnetic field, which can be measured using a measurement technique that is established for biomagnetic investigations. Using the established concepts for magnetic source localization, the three dimensional localization and orientation as well as the strength of the magnetic source can be reconstructed from these magnetic measurement data as a function of time. Furthermore, it is possible to gain quantitative information on the disintegration of dosage forms in vivo. Examples are given for results obtained concerning the esophageal transit, the gastric and the intestinal behavior of capsules and tablets.

Capsules↗

PubMed2005

Gastric perception thresholds are low and sensory neuropeptide levels high in helicobacter pylori-positive functional dyspepsia.

BACKGROUND AND AIMS: In functional dyspepsia (FD) decreased perception levels can be shown on gastric distension. Substance P (SP) and calcitonin gene-related peptide (CGRP) are involved in the sensitization of afferent neuronal pathways due to chronic inflammation. The role of Helicobacter pylori-induced gastric mucosal inflammation in the pathogenesis of FD is controversial. The aim of this study was to assess whether FD patients have altered mucosal concentrations of CGRP and SP, and to investigate whether this is associated with visceral hypersensitivity or H. pylori infection. METHODS: Gastrointestinal symptoms, H. pylori status, perception thresholds at gastric balloon distension, and gastric mucosal concentrations of CGRP and SP were determined in 13 FD patients and 18 healthy controls (HC). RESULTS: In H. pylori-positive FD patients discomfort and pain thresholds on gastric distension were lower compared to other groups. Antral mucosal levels of CGRP and SP were higher in H. pylori-positive subjects. In FD significantly negative correlations between discomfort and pain thresholds and antral mucosal concentrations of CGRP and SP were observed. CONCLUSIONS: In FD low perception thresholds on gastric distension are associated with high levels of CGRP and SP in the antrum, suggesting that sensory neuropeptides are involved in FD pathophysiology.

Adolescent↗

PubMed2005

Excitatory stimulation of neurons in the arcuate nucleus initiates central CRF-dependent stimulation of colonic propulsion in rats.

It is well established that autonomic control of digestive function is modulated by central autonomic neurotransmission. In this context it has been shown that digestive function can be modulated by exogenous neuropeptides microinjected into specific brain sides. Furthermore, there is considerable evidence suggesting that neurons projecting from the arcuate nucleus (ARC) to the PVN may be the source of endogenous neuropeptide release in the PVN. Neuronal projections from the ARC have been proposed to target corticotropin-releasing factor (CRF)-positive neurons in the PVN. Exogenous CRF in the PVN has been shown to modulate digestive function like gastric acid secretion and GI motility. Recently we have demonstrated that activation of ARC neurons inhibits gastric acid secretion via central CRF receptor dependent mechanisms. This poses the question whether neuronal activation of the ARC alters digestive function beside gastric acid secretion. In the present study we investigated whether CRF pathways in the ARC-PVN axis are involved in the modulation of colonic motility. First we examined the effect of an excitatory amino acid, kainate, microinjected into the ARC on colonic motility in anesthetized rats. Colonic motility was measured with a non-absorbable radioactive marker using the geometric center method. Kainate (120 pmol/rat) bilaterally microinjected into the ARC induced a significant stimulation of colonic propulsion. To assess the contribution of hypothalamic CRF to the effects of neuronal stimulation in the ARC on colonic motility we performed consecutive bilateral microinjections of an antagonist to CRF receptors into the PVN and the excitatory amino acid kainate into the ARC. Microinjection of the non-selective CRF receptor antagonist, astressin (100 ng), into the PVN abolished the stimulatory effect of neuronal activation in the ARC by kainate on colonic motor function. The data indicate that activation of neurons in the ARC stimulates colonic motility via CRF-receptor-mediated mechanism in the PVN and underlines the important role of the ARC-PVN circuit for the integrative CNS regulation of GI function.

Animals↗

PubMed2004

CCK inhibits the orexigenic effect of peripheral ghrelin.

CCK and ghrelin exert antagonistic effects on ingestive behavior. The aim of the present study was to investigate the interaction between ghrelin and CCK administered peripherally on food intake and neuronal activity in specific hypothalamic and brain stem nuclei, as assessed by c-Fos-like immunoreactivity (c-FLI) in nonfasted rats. Ghrelin (13 microg/kg body wt) injected intraperitoneally significantly increased the cumulative food intake when measured at 30 min and 1 h after injection, compared with the vehicle group (2.9 +/- 1.0 g/kg body wt vs. 1.2 +/- 0.5 g/kg body wt, P < 0.028). Sulfated CCK octapeptide (CCK-8S) (2 or 25 microg/kg body wt) injected simultaneously blocked the orexigenic effect of ghrelin (0.22 +/- 0.13 g/kg body wt, P < 0.001 and 0.33 +/- 0.23 g/kg body wt, P < 0.0008), while injected alone, both doses of CCK-8S exerted a nonsignificant trend to reduce food intake. Ghrelin (13 microg/kg body wt ip) markedly increased the number of c-FLI-positive neurons per section in the arcuate nucleus (ARC) compared with vehicle (median: 31.35 vs. 9.86, P < 0.0001). CCK-8S (2 or 25 microg/kg body wt ip) had no effect on neuronal activity in the ARC, as assessed by c-FLI (median: 5.33 and 11.21 cells per section), but blocked the ghrelin-induced increase of c-fos expression in this area when both peptides were administered simultaneously (median: 13.33 and 12.86 cells per section, respectively). Ghrelin at this dose had no effect on CCK-induced stimulation of c-fos expression in the paraventricular nucleus of the hypothalamus and the nucleus of the solitary tract. These results suggest that CCK abolishes ghrelin-induced food intake through dampening increased ARC neuronal activity.

Animals↗

PubMed2004

The construction of a new evaluative GERD questionnaire - methods and state of the art.

Gastroesophageal reflux disease (GERD) is one of the most prevalent diseases worldwide, and it is becoming increasingly important to monitor the effect of various interventions on GERD symptoms. There can be rapid temporal changes in the severity and frequency of patients' symptoms as well as their health status and well-being, all of which could, theoretically, be monitored using diaries or questionnaires. However, current GERD monitoring instruments are not appropriate because they do not assess symptoms daily, they are not sufficiently responsive to short-term changes in health status or they are not adequately validated. To address these problems, the conceptual and psychometric requirements for a GERD symptom assessment questionnaire were identified. A dimension-based scale was designed to reduce the number of symptoms monitored on a daily basis, and the validation process was defined to produce parallel long and short forms of a scale for patients' self-assessment of their GERD symptom response to therapy. These basic principles which underlie the successful development of a new, self-assessed symptomatic reflux questionnaire (ReQuest(TM)) are also applicable to the development of validated questionnaires for daily symptom self-assessment in other disease areas.

Gastroesophageal Reflux↗

PubMed2004

Two immunocytochemical protocols for immunofluorescent detection of c-Fos positive neurons in the rat brain.

The immediate-early-gene product c-Fos is a well known marker of neuronal activation in the central nervous system. Thus, immunocytochemical methods to detect c-Fos in the brain are important tools in experimental studies that aim to map activated brain areas on a cellular level. Accordingly, we describe here two alternative protocols for c-Fos detection which are based on an indirect immunofluorescence technique. In fact, both methods allow an excellent and specific visualisation of c-Fos immunoreactive neurons in brain areas, e.g. the hypothalamus. The first protocol is more economical and faster in its execution and useful for observing brain sections using a confocal laser scanning microscope with the intention to perform doublestaining, since in all optical magnification steps (10x-63x) only a low unspecific background staining is visible. Furthermore, this method yields even fluorescent signals which are not detectable with a conventional fluorescence-microscope at lower magnification (10x). The second protocol contains an additional signal amplification step and allows signal detection also with a conventional fluorescence-microscope at lower magnification (10x); it is useful for rapid quantification of c-Fos immunoreactive neurons in the rat brain, but because of moderate unspecific background staining at higher magnification it is less suitable for doublestaining.

Animals↗

PubMed2003

Intraperitoneal injection of ghrelin induces Fos expression in the paraventricular nucleus of the hypothalamus in rats.

Ghrelin is a 28-amino acid peptide hormone secreted from the stomach that acts as a gut-brain peptide with potent stimulatory effects on food intake. The aim of the present study was to investigate the effects of peripheral ghrelin (1 and 10 nmol/rat) injected intraperitoneally (i.p.) on food intake and neuronal activity in the hypothalamus and brain stem, as assessed by c-Fos-like-immunoreactivity (c-FLI), using a confocal laser scanning microscope (cLSM) as a sensitive microscopic technique to detect c-FLI-positive neurons. Cumulative food intake was significantly increased 5.3- and 3.7-fold for the 4-h period after i.p. injection of ghrelin at both doses. The number of c-FLI-positive neurons in the paraventricular nucleus of the hypothalamus (PVN) was significantly increased after peripheral administration of ghrelin (1 nmol i.p.; median: 41.8) compared with i.p. saline (median: 17.5). As described before, c-fos expression was increased in the arcuate nucleus of the hypothalamus (ARC). In the nucleus of the solitary tract (NTS) or the area postrema (AP), there was no significant change in the density of c-FLI-positive neurons. Our data suggest that an activation of the arcuate-paraventricular axis may be part of the brain circuits involved in the orexigenic effect of peripheral ghrelin.

Animals↗

PubMed2003

Stimulation of neurons in rat ARC inhibits gastric acid secretion via hypothalamic CRF1/2- and NPY-Y1 receptors.

Neuropeptide Y (NPY) neuronal projections from the arcuate nucleus (ARC) have been proposed to target corticotropin-releasing factor (CRF)-positive neurons in the paraventricular nucleus (PVN) as part of the ARC-PVN axis. The existence of a positive feedback loop involving CRF receptors in the PVN has been suggested. Exogenous NPY and CRF in the PVN have been shown to inhibit gastric acid secretion. Recently, we have demonstrated that activation of ARC neurons inhibits gastric acid secretion via vagal pathways. To what extent NPY- and CRF-mediated mechanisms in the PVN contribute to the CNS modulation of gastric acid secretion is still an open question. In the present study, we performed consecutive bilateral microinjections of antagonists to NPY receptor subtypes Y1 and Y2 and to CRF1/2 receptors in the PVN and of the excitatory amino acid kainate in the ARC to assess the role of NPY- and CRF-mediated mechanisms in the kainate-induced effects on gastric acid secretion. Gastric acid secretion was measured at the basal condition and during pentagastrin (16 microg/kg body wt) stimulation. Microinjection of vehicle in the PVN and kainate in the ARC decreased gastric acid secretion. Microinjection of the specific NPY-Y1 receptor antagonist BIBP-3226 (200 pmol) and the nonspecific CRF1/2 antagonist astressin (30 pmol) in the PVN abolished the inhibitory effect of neuronal activation in the ARC by kainate on gastric acid secretion. The CRF antagonist astressin was more effective. Pretreatment with the NPY-Y2 receptor antagonist BIIE-0246 (120 pmol) in the PVN had no significant effect. Our results indicate that activation of neurons in the ARC inhibits gastric acid secretion via CRF1/2 and NPY-Y1 receptor-mediated pathways in the PVN.

Animals↗

PubMed2003

Differential induction of c-fos expression in brain nuclei by noxious and non-noxious colonic distension: role of afferent C-fibers and 5-HT3 receptors.

Experimental animal models have been established to gain insight into the pathogenesis and the mechanisms of visceral hyperalgesia in the irritable bowel syndrome (IBS). However, data about the mechanisms and pathways involved in the induction of neuronal activity in forebrain and midbrain structures by a physiological GI stimulus, like colonic distension (CD), in the range from non-noxious to noxious intensities are scarce. Thus, the effect of proximal CD with non-noxious (10 mmHg) and noxious (40 and 70 mmHg) stimulus intensities on neuronal activity in brain nuclei, as assessed by c-fos expression, was established. In additional studies, the role of vagal and non-vagal afferent sensory C-fibers and 5-HT(3) receptors in the mediation of visceral nociception was investigated in this experimental model at noxious colonic distension (70 mmHg). At CD, the number of c-Fos like immunoreactivity (c-FLI)-positive neurons increased pressure-dependently in the nucleus of the solitary tract (NTS), rostral ventrolateral medulla (RVLM), nucleus cuneiformis (NC), periaqueductal gray (PAG), and the amygdala (AM). In the dorsomedial (DMH) and ventromedial nucleus (VMH) of the hypothalamus, as well as in the thalamus (TH), neuronal activity was also increased after CD, but independently of stimulus intensities. A decrease of the CD-induced c-fos expression after sensory vagal denervation by perivagal capsaicin treatment was only observed in brainstem nuclei (NTS and RVLM). In all other activated brain nuclei examined, the CD-related induction of c-fos expression was diminished only after systemic neonatal capsaicin treatment. In the NTS and RVLM, a trend of decrease of c-fos expression was also observed after systemic neonatal capsaicin treatment. In order to assess the role of the 5-HT(3) receptor in CD-induced neuronal activation of brain nuclei, animals were pretreated with the 5-HT(3) receptor antagonist granisetron (1250 microg/kg, i.p. within 18 h before CD). Pretreatment with granisetron significantly reduced the number of c-FLI-positive cells/section in the NTS by 40%, but had no significant effect on the CD-induced c-fos expression in other brain areas. The data suggest that distinct afferent pathways and transmitters are involved in the transmission of nociceptive information from the colon to the brain nuclei activated by proximal colonic distension. Activation of NTS neurons at such a condition seems to be partially mediated via capsaicin-sensitive vagal afferents and 5-HT(3) receptors. In contrast, activation of brain nuclei in the di- and telencephalon by nociceptive mechanical stimulation of the proximal colon, as assessed by c-fos expression, is partially mediated by capsaicin-sensitive, non-vagal afferents, and independent of neurotransmission via 5-HT(3) receptors. The modulation of CD-induced c-fos expression exclusively in the NTS by granisetron points to a role of 5-HT(3) receptor antagonists in the modulation of vago-vagal sensomotoric reflexes rather than an influence on forebrain nuclei involved in nociception.

Afferent Pathways↗