H Mönnikes

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.

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.

Peripheral obestatin has no effect on feeding behavior and brain Fos expression in rodents

Obestatin is produced in the stomach from proghrelin by post-translational cleavage. The initial report claimed anorexigenic effects of obestatin in mice. Contrasting studies indicated no effect of obestatin on food intake (FI). We investigated influences of metabolic state (fed/fasted), environmental factors (dark/light phase) and brain Fos response to intraperitoneal (ip) obestatin in rats, and used the protocol from the original study assessing obestatin effects in mice. FI was determined in male rats injected ip before onset of dark or light phase, with obestatin (1 or 5 micromol/kg), CCK8S (3.5 nmol/kg) or 0.15 M NaCl, after fasting (16 h, n=8/group) or ad libitum (n=10-14/group) food intake. Fos expression in hypothalamic and brainstem nuclei was examined in freely fed rats 90 min after obestatin (5 micromol/kg), CCK8S (1.75 nmol/kg) or 0.15 M NaCl (n=4/group). Additionally, fasted mice were injected ip with obestatin (1 micromol/kg) or urocortin 1 (2 nmol/kg) 15 min before food presentation. No effect on FI was observed after obestatin administration during the light and dark phase under both metabolic conditions while CCK8S reduced FI irrespectively of the conditions. The number of Fos positive neurons was not modified by obestatin while CCK8S increased Fos expression in selective brain nuclei. Obestatin did not influence the refeeding response to a fast in mice, while urocortin was effective. Therefore, peripheral obestatin has no effect on FI under various experimental conditions and did not induce Fos in relevant central neuronal circuitries modulating feeding in rodents.

Electrogastrography as a diagnostic tool for delayed gastric emptying in functional dyspepsia and irritable bowel syndrome

Several pathophysiological mechanisms have been proposed in functional gastrointestinal (GI) disorders, e.g. altered GI motility and sensitivity. The aim of this study was to investigate gastric electrical activity (GEA) in patients with functional dyspepsia (FD) or irritable bowel syndrome (IBS) compared with healthy controls (HC), and to assess if abdominal symptoms and delayed gastric emptying are associated with alterations in GEA, as determined by electrogastrography (EGG). Forty patients with FD, IBS or both were compared with 22 HC. EGG was performed before and after a standard meal. Frequencies and amplitudes pre‐ and post‐prandially were analysed. Furthermore, gastric emptying and symptom scores were assessed. Eight of 40 patients (20%; three FD, three IBS, two FD and IBS) had delayed gastric emptying. Disturbed gastric emptying and lack of a postprandial increase in the EGG amplitude were significantly correlated (ru2003=u20030.8; Pu2003<u20030.005). No differences between controls and patients were observed in the distribution of EGG frequencies. Treatment with the prokinetically active macrolide erythromycin improved gastric emptying, GEA and symptoms (nu2003=u20034). The data suggest that EGG could be useful as a diagnostic tool in patients with FD and IBS to identify a subgroup of patients with delayed gastric emptying.

Cocaine- and amphetamine-regulated transcript stimulates colonic motility via central CRF receptor activation and peripheral cholinergic pathways in fed, conscious rats

Abstractu2002 Many neuropeptides participating in the hypothalamic control of feeding behaviour and satiety have been shown to be additionally involved in the autonomic control of gastrointestinal (GI) functions. Recently, the neuropeptide cocaine‐ and amphetamine‐regulated transcript (CART) has been indicated to function as an anorectic substance in the brain. In the present study we examine the hypothesis that CART is involved in the modulation of GI motility. Colonic transit time was measured after peripheral and central injection of CART in fed and freely moving Sprague–Dawley rats. Intracerebroventricular injection of synthetic CART (55‐102) (190u2003pmol and 1.9u2003nmol per 10u2003μL and saline controls) decreased the colonic transit time of conscious rats up to 46%. In contrast, i.p. injection of CART (55‐102) (1.9u2003nmol and 19u2003nmolu2003kg−1 BW and saline controls) had no effect on colonic motility. Central administration of a CRF receptor antagonist (2.8u2003nmol) prior to central CART administration antagonized the CART‐induced stimulation of colonic transit. Pretreatment with the peripherally acting cholinergic antagonist atropin methyl nitrate (0.1u2003mgu2003kg−1 i.p.) blocked the stimulatory CART effect on colonic motor function. The results suggest that CART acts in the central nervous system to modulate behavioural motor function via a central CRF receptor‐dependent mechanism and peripheral cholinergic pathways.

Excitatory stimulation of neurons in the arcuate nucleus inhibits gastric acid secretion via vagal pathways in anesthetized rats.

It is well established that autonomic control of gastrointestinal function is modulated by central autonomic neurotransmission. In this context it has been shown that gastrointestinal motility and secretion can be modulated by exogenous neuropeptides microinjected into the paraventricular nucleus of the hypothalamus (PVN). 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. This poses the question whether stimulation of neurons in the arcuate nucleus, e.g. by an excitatory amino acid, alters gastrointestinal function. In the present study, we investigated the effect of an excitatory amino acid, kainate, microinjected into the arcuate nucleus on gastric acid secretion in urethane-anesthetized rats. Kainate (140 pmol/rat) bilaterally microinjected into the Arc induced an significant inhibition of pentagastrin (PG) stimulated (16 mg/kg per h) gastric acid secretion throughout an observation period of 120 min after microinjection. Microinjection of kainate into hypothalamic areas outside the arcuate nucleus did not modify gastric secretion. Bilateral cervical vagotomy blocked the effect of kainate injected into the Arc on PG-stimulated gastric acid secretion. These data show that gastric secretory function can be modulated by stimulation of neuronal activity in the Arc via efferent vagal pathways. The results suggest that the arcuate nucleus is a forebrain area involved in the CNS regulation of gastrointestinal function.

Ösophageale Refluxdiagnostik – pH-Metrie, Impedanzmessung, Bilirubin-Messung: Empfehlungen der Deutschen Gesellschaft für Neurogastroenterologie und Motilität und der Arbeitsgruppe Neurogastroenterologie der Deutschen Gesellschaft für Verdauungs- und Stoffwechselkrankheiten

The current recommendations on indications, technical performance, and interpretation of diagnostic techniques for oesophageal reflux update the German recommandations about 24 hour pH measurement of 2003. The recommendations encompass conventional pH measurement, wireless pH measurement, pH and impedance measurements, and bilirubin measurement (duodenogastro-oesophageal reflux).

Chronische Obstipation@@@Chronic constipation: Rationales Management bei Erwachsenen@@@Rational management in adults

ZusammenfassungDas Symptom der Obstipation zählt zu den häufigsten chronischen Beschwerden aller Altersgruppen weltweit. Die Ursachen reichen von genetisch determinierten oder erworbenen Störungen der Funktionen des Gastrointestinaltrakts oder Beckenbodens über die Auslösung durch Erkrankungen, bei denen die Obstipation ein Sekundärphänomen ist, bis hin zur Folge medizinischer Therapien oder persönlicher Lebens- und Verhaltensweisen. Die geringe Spezifität der Ursache bei großer Variabilität der Schwere mag dazu beitragen, dass – trotz der daraus oft resultierenden gravierenden Einschränkung der Lebensqualität – der Obstipation zumeist kein angemessener Krankheitswert zuerkannt wird. Zu dieser Tatsache tragen Tabuisierung, Frustration über den mäßigen Therapieerfolg und ökonomisch motivierte Grenzziehungen durch Kostenträger bei. Deshalb ist ein rationales, evidenzbasiertes Management der Diagnostik und Therapie beim „Volkssymptom“ Obstipation sehr wichtig. Die aktuell publizierte S2k-Leitlinie Chronische Obstipation, an der sich diese Übersicht orientiert, kann helfen, dieser Herausforderung gerecht werden zu können.AbstractConstipation is one of the most common chronic complaints in all age groups worldwide. Reasons are manifold, encompassing genetic or acquired functional disabilities of the gastrointestinal tract or pelvic floor, secondary phenomena due to other diseases, pharmacological side effects or personal way of life. The low causal specificity and high variability of symptom severity as well as misinformation, frustration about lacking therapeutic success and economically motivated factors may contribute to the circumstance that chronic constipation, although resulting in serious reduction of quality of life, is still not or rarely considered a disease of clinical significance. Therefore, a rational, evidence-based management of diagnostics and therapy of this widespread symptom is important. This review which is based on the recently published German S2k guidelines on chronic constipation will help to meet this challenge.