[Chest pain - not always the heart! Clinical impact of gastrointestinal diseases in non-cardiac chest pain]. / Brustschmerz - nicht immer das Herz! Klinische Bedeutung gastrointestinaler Erkrankungen beim nicht-kardialen Thoraxschmerz.

Non cardiac chest pain (NCCP) are recurrent angina pectoris like pain without evidence of coronary heart disease in conventional diagnostic evaluation. The prevalence of NCCP is up to 70 % and may be detected in this order at all levels of the medical health care system (general practitioner, emergency department, chest pain unit, coronary care). Reduction of quality of life in NCCP is comparable, partially even higher compared to cardiac chest pain. Reasons for psychological strain are symptom recurrence in app. 50 %, nonspecific diagnosis with resulting uncertainty and insufficient integration of other medical disciplines in diagnostic work-up. Managing of patients with NCCP has to be interdisciplinary because non cardiac causes of chest pain may be found frequently. Especially gastroenterological expertise is required because in 50 - 60 % of cases gastroesophageal reflux disease (GERD), in 15 - 18 % hypercontractile esophageal motility disorders with nutcracker, jackhammer esophagus or distal esophageal spasmus or achalasia and in 32 - 35 % other esophageal alterations (e. g. infectious esophageal inflammation, drug-induced ulcer, rings, webs, eosinophilic esophagitis) as cause of chest pain may be detected. This implicates that regular interdisciplinary round wards and management of chest pain units are mandatory.

[Sphincter of Oddi dyskinesia]. / Sphinkter-Oddi-Dyskinesie.

Sphincter of Oddi dyskinesia is a functional disorder of the papillary region which can lead to clinical symptoms due to functional obstruction of biliary and pancreatic outflow. Based on the severity of the clinical symptoms the disorder can be graded into three types (biliary and pancreatic types I-III). The manometric diagnosis of this disorder using sphincter of Oddi manometry is hampered by the relatively high risk of pancreatitis after endoscopic retrograde cholangiopancreatography. Although papillary manometry is often carried out in North America, in Europe this is the exception rather than the rule. Manometrically, sphincter of Oddi dyskinesia is characterized by an increased pressure in the biliary and/or the pancreatic sphincter segments and can be treated by endoscopic papillotomy. This overview counterbalances the arguments for primary invasive diagnostics and a pragmatic clinical approach, i.e. papillotomy should be directly carried out when a sphincter of Oddi dyskinesia is clinically suspected. For patients with biliary or pancreatic type I, endoscopic papillotomy is the treatment of choice. In biliary type II sphincter of Oddi manometry could be helpful for clinical decision-making; however, the exact risk-benefit ratio is still difficult to assess. In type III patient selection and the low predictive value of manometry for treatment success questions the clinical usefulness of sphincter of Oddi manometry.

[Diagnosis of oesophageal reflux by PH, impedance, and bilirubin measurement: recommendations of the German Society of Neurogastroenterology and of the working group for neurogastroenterology of the German Society for Digestive and Metabolic Diseases]. / 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).

Differential stimulatory effects of cannabinoids on VIP release and NO synthase activity in synaptosomal fractions from rat ileum.

Cannabinoid-1 (CB1) and CB2 receptors are present on neurons of the enteric nervous system. Our aim was to study whether cannabinoid receptor activation is involved in the regulation of VIP release and NO synthesis in isolated fractions of nerve terminals from rat ileum. VIP was measured by RIA and NO synthesis was analyzed using a L-[3H]arginine assay. Anandamide stimulated VIP release (basal: 245.9+/-12.4pg/mg, 10(-6)M: 307.6+/-11.7pg/mg, [n=6, P<0.05], 10(-7)M: 367.0+/-26.1pg/mg, [n=6, P<0.01]). The cannabinoid receptor agonist WIN 55,212-2 had similar effects (basal: 250.5+/-37.4pg/mg, 10(-6)M: 320.9+/-34.7pg/mg; [n=4, P<0.05]). The stimulatory effect of anandamide was blocked by the selective CB2 receptor antagonist, SR144528 (10(-7)M) (anandamide 10(-6)M: 307.6+/-11.7pg/mg; +SR144528: 249.0+/-26.3pg/mg, [n=6, P<0.05]), whereas the selective CB1 receptor antagonist SR141716 A had no effect. NO synthesis was stimulated by anandamide ([fmol/mg/min] basal: 0.08+/-0.01, 10(-6)M: 0.16+/-0.03; 10(-7)M: 0.13+/-0.02, n=4, P<0.05) and WIN 55,212-2 ([fmol/mg/min] basal: 0.05+/-0.01, 10(-6)M: 0.1+/-0.02, n=4, P<0.05). The anandamide reuptake inhibitor, AM 404 increased basal NOS activity ([fmol/mg/min] control: 0.1+/-0.04, 10(-6)M: 0.28+/-0.08, n=7, P<0.05). The stimulatory effect of anandamide on NO synthase was not antagonized by antagonists at the CB1, CB2 or TRPV1 receptor, respectively. In conclusion, in enteric nerves anandamide stimulates VIP release by activation of a CB2 receptor specific pathway, while the stimulation of NO production suggests the existence of an additional type of cannabinoid receptor in the enteric nervous system.

Do we need gastric acid?

Evidence from comparative anatomy and physiology studies indicates that gastric acid secretion developed during the evolution of vertebrates approximately 350 million years ago. The cellular mechanisms that produce gastric acid have been conserved over the millennia and therefore proton pump inhibitors have pharmacological effects in almost all relevant species. These observations suggest that gastric acid provides an important selective advantage; however, in modern-day humans the need for gastric acid can be questioned in light of the widespread use of safe and effective pharmacologic acid suppression. The Kandahar Working Group addressed questions concerning the need, production and effects of gastric acid, specifically: (1) motility in the upper gastrointestinal (GI) tract; (2) neuroendocrine factors; (3) digestive and mucosal processes; (4) microbiology, and (5) central processes and psychological involvement. We addressed each topic with the individual models available to answer our questions including animal versus human studies, pharmacologic, surgical as well as pathophysiologic states of acid suppression.

Are Downhill Varices an Overlooked Entity of Upper Gastrointestinal Bleedings?

AIM: Downhill varices are not so safe as thought and can lead to life-threating or mortal bleeding complication, even if rare. In order to draw attention to this topic, we analysed 129 patients. MATERIALS AND METHODS: We evaluated the electronic endoscopy data records of all patients undergoing upper gastrointestinal endoscopy over a nine-year period from January 2004 till December 2012, within a retrospective approach. The primary endpoints, incidence, causes, kind of resulting upper gastrointestinal bleeding, and the severity of the bleeding were evaluated. Secondary endpoints were the evaluation of the size of downhill varices and a comparison of the risk of bleeding between downhill varices and uphill varices. RESULTS: Downhill varices were identified, described, and/or documented in 129 patients of 25,680 upper gastrointestinal endoscopies. 26 patients had central venous catheter or port implantation, 22 patients had a history of an implantation of a cardiac pacemaker, 7 patients had severe pulmonary artery embolism, and 4 patients had severe chronic obstructive pulmonary disease. Two patients had mediastinal tumors, and one patient had a large retrosternal goiter as a possible cause of the vena cava syndrome. Altogether, 62 patients were related to a vena cava superior syndrome; 67 were not. CONCLUSIONS: Downhill varices can be seen with an incidence of 0.5%. Therapeutic means are the banding therapy as a safe and effective option. Severe bleedings associated with downhill varices can be mortal. Severe forms of downhill varices should be examined in relation to the origin in order to start a specific therapy.

Cannabinoid type 1 receptor modulates intestinal propulsion by an attenuation of intestinal motor responses within the myenteric part of the peristaltic reflex.

Cannabinoid-1 (CB1) receptor activation affects gastrointestinal propulsion in vivo. It was our aim to further characterize the involved myenteric mechanisms in vivo and in vitro. In CB1(-/-) mice and wild-type littermates we performed in vivo transit experiments by charcoal feeding and in vitro electrophysiological recordings in mouse small intestinal smooth muscle. Ascending neuronal contraction (ANC) following electrical field stimulation was studied in rat ileum in a partitioned organ bath separating the aboral stimulation site from the oral recording site. The knockout animals displayed an accelerated upper gastrointestinal transit compared to control animals. The CB1 receptor antagonist AM251 stimulated the force of the ANC in a concentration dependent manner when added in the oral chamber. Anandamide significantly inhibited the ANC when added in the oral chamber. Neither AM251 nor anandamide had an influence on the contraction latency. No effects were observed when drugs were added in the aboral chamber, proving a CB1 mediated action on the neuromuscular junction. Resting membrane potentials and neuronal induced inhibitory junction potentials in CB1(-/-) mice were unchanged as compared to wild type. However, the electrophysiological slow waves were more sensitive to blockade of Ca(2+) channels in CB1(-/-) mice. Our data strongly suggest a physiological involvement of the CB-1 receptor in the regulation of small intestinal motility. Therefore, CB1 receptors are a promising target for the treatment of motility disorders.

CB1 and TRPV1 receptors mediate protective effects on colonic electrophysiological properties in mice.

CB1 and TRPV1 receptors modulate enteric neurotransmission and colonic inflammation. This study investigates early electrophysiological changes in distal colon of wild-type and receptor deficient mice after an inflammatory insult set by dinitrobenzene sulfonic acid (DNBS). Colitis was induced by DNBS in CB1(-/-) mice, TRPV1(-/-) mice, and their respective wild-type littermates. Electrophysiological properties consisting of membrane potentials and electrically induced inhibitory junction potentials (IJP) of circular smooth muscle cells were evaluated at different time points. Additionally a histological colitis severity score was evaluated in CB1(+/+) and CB1(-/-) mice 24 h after DNBS. Inflammation caused spontaneous atropine insensitive rhythmic action potentials in CB1(-/-) and TRPV1(-/-) mice but not in wild-type animals. This indicates that membrane stability is disturbed, which in turn indicates a lack of protective mechanisms. Focal electrical neuronal stimulation of the myenteric plexus induced IJP in the smooth muscle cells. Twenty-four hours after initiation of inflammation, the duration of the IJP is prolonged in all animals, indicating disturbances within neuromuscular interaction. In CB1(-/-) mice, it is interesting that the duration of IJP was significantly extended, as compared to CB1(+/+) mice pointing toward missing protective mechanisms in the CB1(-/-) mice. Inflammatory insults in the mouse colon induce reproducible changes in the electrophysiological properties and such changes correlate with duration of colitis. In mutants, these electrophysiological changes display different patterns, suggesting the lack of protective properties for neuromuscular interactions and membrane stability.

Efficacy and safety of cold snare resection in preventive screening colonoscopy.

BACKGROUND AND AIM: Removal of polyps during colonoscopy effectively prevents the development of colorectal cancer. So far, snare resection with high frequency current with or without prior submucosal saline injection is the method of choice. The aim of this study was to evaluate the feasibility, safety, and outcome of cold snare resection during routine endoscopy. METHODS: In this prospective study, 522 patients undergoing outpatient colonoscopy were included. Cold snare resection for diminutive (< 6 mm), small (6 - 9 mm), and larger polyps (> 9 - 15 mm) was performed using a dedicated cold snare device (Exacto ® ) without prior submucosal injection. Outcome parameters included bleeding rate, perforation rate, procedure time, histologic evaluation of polyp margins, and success rates. The data were compared to a group of patients undergoing hot snare resection. RESULTS: Overall, 1233 polyps were removed using cold snare resection with an overall success rate of 99.4 %. All failures of cold snare resection occurred in the cecum (8/82, failure rate 9.8 %). In the remaining colon, the success rate was 100 %. Immediate post-polypectomy bleeding occurred in 0.49 % of all patients and was most frequently seen in polyps larger than 9 mm. The procedure time was significantly shorter using cold snare resection compared with hot snare resection (27.6 min vs. 35.7 min, P  < 0.01). CONCLUSION: Cold snare resection can be performed safely in outpatients for removal of small polyps in screening colonoscopy. It does not require prior saline injection and reduces procedure time without an increased risk of bleeding.

The selective metabotropic glutamate receptor 5 antagonist mavoglurant (AFQ056) reduces the incidence of reflux episodes in dogs and patients with moderate to severe gastroesophageal reflux disease.

BACKGROUND: Transient lower esophageal sphincter relaxations (TLESRs) induced by gastric distension are modulated by the metabotropic glutamate receptor 5 (mGluR5) that influences the vagal reflex loop. We therefore aimed to examine the effects of the selective mGluR5 antagonist mavoglurant (AFQ056) on the number of TLESRs in dogs and reflux episodes in patients with gastroesophageal reflux disease (GERD). METHODS: In a dog model, the number of meal-induced TLESRs was determined after intravenous (0.03, 0.1, 0.3, and 1 mg kg-1 ) and oral (1, 3, and 10 mg kg-1 ) doses of mavoglurant with reference to vehicle. In a multicenter, randomized, double-blind, placebo-controlled, three-period crossover study, the incidence of meal-induced reflux episodes was assessed by esophageal impedance monitoring after single, oral doses of mavoglurant (50 and 400 mg) or baclofen (40 mg) in 30 patients with moderate to severe GERD. KEY RESULTS: In dogs, mavoglurant reduced the number of TLESRs after intravenous and oral administration. In patients with GERD, the incidence of postprandial reflux episodes was significantly lower at a dose of 400 mg mavoglurant (-37.5% ; 90% confidence interval [CI]: -57.8, -17.2), whereas there was no significant difference at 50 mg of mavoglurant compared to placebo. A significantly lower incidence of reflux episodes was also noted with the active comparator baclofen (-50.3%; 90% CI: -66.2, -34.3), thereby validating this study. CONCLUSIONS AND INFERENCES: These data suggest a potential clinical benefit of mGluR5 antagonists such as mavoglurant in patients with GERD, particularly in those with persisting symptoms despite treatment with proton pump inhibitors.

Effect of motilin on gastric emptying in patients with diabetic gastroparesis.

OBJECTIVES: Because disturbances of gastric emptying are a serious complication in insulin-dependent diabetic subjects with regard to the maintenance of good metabolic control, we wanted to assess the effectiveness of motilin as a potential treatment for gastric emptying disturbances. RESEARCH DESIGN AND METHODS: The intestinal hormone motilin has been shown to accelerate gastric emptying in healthy subjects. Therefore, we examined the effect of intravenous motilin on gastric emptying of a 99mTc colloid-labeled semisolid test meal in 9 insulin-dependent diabetic patients with diabetic gastroparesis. All patients had a significantly delayed gastric emptying rate compared with a group of 11 healthy control subjects. RESULTS: During the infusion of motilin, gastric emptying was accelerated, and it was no longer significantly different from control values. CONCLUSIONS: These data demonstrate that motilin and related compounds such as erythromycin derivatives could be useful for the treatment of disturbed gastric emptying in diabetic subjects.

Endogenous CCK depresses contractile activity within the ascending myenteric reflex pathway of rat ileum.

The ascending excitatory reflex is an important part of the myenteric reflex. In order to study the ascending neural pathways, isolated segments of rat ileum were stimulated by electrical stimulation of the gut wall (20 V, 3 pulses per second, 1 ms) using platinum electrodes. The excitatory contractile response was recorded using perfused manometric side-hole tubing located 2 and 4 cm orally to the stimulation site. The contractile response to electrical stimulation was abolished by atropine (10(-6) M) or hexamethonium (10(-4) M). The excitatory response increased after administration of the cholecystokinin A (CCK(A)) receptor antagonists lorglumide (3x10(-6) M: +44.1%), devazepide (10(-8) M: +19.4%; 10(-7) M: +30.0%) and SR-27897 (10(-10) M: +21.8%, 10(-8) M: +47.0%, P<0.05, n=8). However, the CCK(B) receptor antagonist L-365,260 also caused a significant increase in the oral excitation (10(-6) M: +27.4%). sCCK-8 caused a significant reduction in the ascending response (10(-8) M: -11.5%) and induced spontaneously occurring contractions at doses ranging from 10(-10)-10(-6) M. CCK-9 significantly increased the ascending response (10(-7) M: +10.9%, P<0.05). However, caerulein (10(-10) M: -25.9%, 10(-8) M: -26.8%; P<0.01) and pentagastrin (10(-10) M: -20.2%, P<0.05; 10(-8) M: -23.7%, P<0.01; 10(-6) M: -28.3%, P<0.001) reduced the ascending contractile response significantly. These data, obtained with potent and highly specific CCK receptor antagonists, demonstrate an inhibitory role of endogenously released CCK within the ascending neural pathway. The data further suggest that exogenously applied CCK-related peptides have different effects on the myenteric reflex which might be due to excitation of the different involved neurons (short and long ascending inter- and motorneurons) in an unphysiological order. Thus in experiments investigating more complex neuronal circuits, experiments with antagonists should be regarded as more specific.

Current concepts on pathophysiology, diagnosis and treatment of diffuse oesophageal spasm.

Diffuse oesophageal spasm is a functional oesophageal motility disorder of unknown aetiology, which appears to be due to a disturbance of the normal pharmacological timing of propulsive contraction occurring in the oesophageal body after swallowing. The lack of pathophysiological understanding may be due to the fact that there is more than one pathophysiological pathway causing symptoms of diffuse oesophageal spasm. Barium studies, oesophageal scintigraphy and fiberoptic examination can be helpful in finding the correct diagnosis, but manometry is still the gold standard of diagnostic procedures. Similar to other spastic oesophageal motility disorders, pharmacological treatment of diffuse oesophageal spasm includes nitrates, calcium antagonists, anticholinergics and antidepressants with varying beneficial effects. Botulinum toxin, which provides sufficient treatment as measured by symptom score and manometric patterns in patients with achalasia, was recently evaluated for the treatment of diffuse oesophageal spasm in small patient selections with promising results.

Canine myenteric, deep muscular, and submucosal plexus preparations of purified nerve varicosities: content and chromatographic forms of certain neuropeptides.

Partially purified nerve varicosities prepared from canine small intestinal myenteric, deep muscular and submucosal plexuses were found to contain, by radioimmunoassay, gastrin-releasing polypeptide (GRP), substance P, Leu-enkephalin, Met-enkephalin, vasoactive intestinal polypeptide (VIP) and neurokinin A, but did not contain detectable amounts of neurokinin B. In all three plexus preparations, VIP was present in the highest concentration. In contrast to other species, GRP and the enkephalins were found to be present in relatively high concentrations in the submucosal plexus and GRP was present in low concentrations in the deep muscular plexus. Equal concentrations of substance P and neurokinin A were found in the myenteric and deep muscular plexus preparations but greater concentrations of substance P relative to neurokinin A were found in the submucosal plexus preparations. On reverse phase HPLC, a major peak of immunoreactivity occurred at the retention times of standard preparations for all six neuropeptides measured. Significant heterogeneity was found for GRP- and VIP-like immunoreactivity, especially in the submucosal plexus preparations. These partially purified canine small intestine nerve varicosity preparations may prove of value in studying release mechanisms for, and the posttranslational processing of, neuropeptides.

The actions of neurokinins and substance P in canine pylorus, antrum and duodenum.

Analogues highly selective for receptors for substance P [beta-Ala4,Sar9,Met(02)11]-SP(4-11), for neurokinin A, [Nle10]-NKA(4-10), and for neurokinin B, [beta-Asp4,MePhe7]-NKB(4-10), were administered intraarterially before and after atropine or tetrodotoxin, to characterize the locations on nerve and muscle of the different receptor subtypes in the canine antrum, pylorus and duodenum. Circular muscle strips from each region were also studied in vitro. The NK-2 receptors in the antrum and the pylorus were located postsynaptically on smooth muscle. The NK-3 receptors, on the other hand, were located on neuronal sites in the antrum and duodenum. NK-1 receptors were located on neuronal and nonneuronal sites in the antrum, pylorus and duodenum. Only nonneural receptors could be activated in vitro.

Effect of endomorphin on somatostatin secretion in the isolated perfused rat stomach.

UNLABELLED: Recently the two peptides endomorphin-1 and -2 were isolated from bovine brain, which are postulated to be endogenous agonists for mu-opiate receptors in the CNS. Since exogenous and endogenous opioids have been shown to influence gastric functions, it was of interest to examine the effects of endomorphin-1 (Tyr-Pro-Trp-Phe-NH(2), EM-1) and -2 (Tyr-Pro-Phe-Phe-NH(2), EM-2) in the isolated perfused rat stomach. RESULTS: EM-1 10(-8) M and 10(-6) M inhibited somatostatin (SLI) levels from a mean of 79 +/- 2.7 pg/min and 73 +/- 2.7 pg/min to 52 +/- 4.0 pg/min (n = 5, n.s.) and 27 +/- 3.0 pg/min (n = 5, P < 0.05), respectively. To characterize the effect on stimulated SLI-secretion, it was prestimulated for 30 min with gastric inhibitory polypeptide (GIP, 10(-9) M). EM-1 decreased prestimulated SLI-secretion in a concentration-dependent manner from a mean of 469 +/- 64.9 pg/min during the immediately preceding 15 minutes to 184 +/- 12.1 pg/min (67 +/- 4.0 %) at 10(-7) M and from a mean of 1146 +/- 269.6 pg/min to 111 +/- 14.1 pg/min (94 +/- 2.2 %) at 10(-6) M (each n = 6, each P < 0.05). In addition EM-2 was also examined at a concentration of 10(-6) M, which inhibited prestimulated SLI-secretion from a mean of 514 +/- 14.9 pg/min to a nadir of 204 +/- 44.7 pg/min (42 +/- 5 %, n = 6, P < 0.05). Application of the specific mu-opiate receptor antagonist CTOP in doses of 10(-7) to 10(-5) M significantly attenuated the inhibitory effect of EM-1 10(-7) M from 67 +/- 4.0 % to 34 +/- 4.7 % (10(-7) M), 33 +/- 3.0 % (10(-6) M) or 30 +/- 8.6 % (10(-5) M), respectively. This residual inhibition, however, was still significantly different from the preceding perfusion period. On the other hand, naloxone 10(-6) M completely abolished the inhibitory effect of EM-1 10(-7) M. Similarly, the inhibitory effect of 10(-6) M EM-1 was also significantly reduced by CTOP from 94 +/- 2.2 % to 60 +/- 10.9 % (10(-7) M), 61 +/- 5.5 % (10(-6) M) or 51 +/- 12.5 % (10(-5) M), respectively, and the residual effect was significantly different from the preceding perfusion period as well. At this higher dose of EM-1 (10(-6) M) naloxone 10(-6) M reduced the effect to 35 +/- 8.2 %, but there was still a significant difference of SLI levels compared to the preceding stimulation period (P < 0.05). Naloxone 10(-6) M reduced the inhibitory effect of EM-2 10(-6) M from 42 +/- 5.0 % to 20 +/- 5.0 % (P < 0.05), which was still significantly different compared to the preceding stimulation period. EM-1 at the doses of 10(-12) M, 10(-10) M, 10(-8) M and 10(-6) M had no significant effect neither on basal gastrin, bombesin (BLI) and vasoactive intestinal polypeptide (VIP) release nor during concomitant infusion of GIP. CONCLUSIONS: EM-1 and -2 inhibit basal and prestimulated SLI secretion in the isolated perfused rat stomach, which is in part attenuated by the mu-receptor antagonist CTOP. The greater inhibitory effect of naloxone, which can be demonstrated at least during the lower dose of EM-1, indicates that other opiate receptors contribute as well. The failure of naloxone to completely antagonize the effect of the higher concentration of EM-1 or EM-2 could be due to insufficient dosage or might indicate the involvement of non-opiate receptor mechanisms.

Modulatory effect of endogenous and exogenous opioids on the excitatory reflex pathway of the rat ileum.

The ascending excitatory reflex is part of the peristaltic reflex, an important participant in intestinal propulsion. The aim of this study was to characterize the role of different opioid receptors in the ascending reflex through exogenous application of non-selective (Met-enkephalin) and selective opioid agonists (mu-PLO17, delta-DPDPE, kappa-U-50, 488) as well as selective opioid receptor antagonists (mu: CTOP-NH(2), delta: ICI-174,864, kappa: Nor-Binaltorphimine). Metenkephalin (IC(50): 0.06 microM) and morphine (IC(50): 1.8 microM) inhibited the ascending reflex response concentration-dependently. Both the mu-selective agonist PLO17 (IC(50): 0.83 microM, n =11) and the kappa-selective agonist U-50,488 (IC(50): 0.68 microM, n =8) concentration-dependently inhibited the magnitude of the ascending contractile reflex response, whereas the delta-agonist DPDPE (10(-10)-10(-6)M) had no significant effect. In contrast, the latency of the response (time interval between start of the stimulus and onset of the contraction) was significantly prolonged by PLO17 > morphine > Met-enkephalin > DPDPE, whereas U-50,488 showed no effect. When the effect of the receptor-specific antagonists was tested, only CTOP-NH(2)and Nor-BNI caused a significant increase of the contractile response, whereas ICI-174 864 was ineffective. On the other hand, CTOP-NH(2)> ICI-174 864 decreased the latency significantly but the kappa-receptor agonist Nor-BNI had no influence. Thus, mu- and kappa-receptors seem to be involved in regulating the contraction strength of the ascending reflex, whereas both mu- and delta-receptors seem to be involved in the timing of the reflex response.

Interaction between endogenous opioids, cholinergic and adrenergic mechanisms during vagally-induced gastrin release in rats.

Endogenous opioids are present in neurons of the vagus and the intrinsic nervous system and they are colocalized with gastrin in antral G-cells. This raises the possibility that endogenous opioids modulate gastrin release. Stimulation of both cervical vagi (10V, 5Hz, 5ms) elicited an increase of arterial plasma gastrin levels at intragastric pH7 or pH2. The response at pH2 was 30% of that at luminal pH7. Atropine reduced vagally stimulated gastrin levels substantially. At luminal pH2 the small residual noncholinergic response was mediated neither by adrenergic mechanisms nor by endogenous opioids. At luminal pH 7 adrenergic blockade with phentolamine and propranolol reduced vagally stimulated gastrin by 60%. In the presence of atropine adrenergic blockade elicited only a small inhibitory effect suggesting that vagal activation of adrenergic mechanisms depends on atropine-sensitive cholinergic pathways. Blockade of opiate receptors by naloxone had no effect on vagal gastrin release, however, the noncholinergic gastrin response was reduced significantly by naloxone, suggesting that cholinergic mechanisms normally restrain activation of endogenous opioids during vagal stimulation. Naloxone had no effect on the noncholinergic, nonadrenergic stimulation of gastrin levels. These data suggest that endogenous opioids can contribute to vagal gastrin release provided the cholinergic restraint is blocked and adrenergic mechanisms stimulate endogenous opioids. In conclusion a major role of endogenous opioids in the regulation of vagal gastrin release can not be detected.

Effect of naloxone on vagally-induced gastric acid secretion in rats.

Previous studies in man and dogs have demonstrated that endogenous opioids participate in the stimulation of cephalic phase gastric acid secretion during indirect activation of the vagus. Since the effect of naloxone during direct vagal activation is unknown gastric acid secretion was assessed during electrical stimulation of the distal cut ends of both vagal nerves. In overnight fasted anesthetized rats the distal ends of the bisectioned cervical vagi were stimulated with 10V, 5Hz, 5 msec for 15 min. Vagal stimulation elicited an increase of gastric acid secretion by 5.6 mumol/min. Naloxone (1 mumol/kg.h) augmented gastric acid secretion significantly. Since this effect of naloxone was in contrast to previous data possible mechanisms of action of naloxone were examined that might help to explain this apparently inhibitory action of endogenous opioids on vagally-induced gastric acid secretion. The additional infusion of atropine or hexamethonium abolished the stimulatory effect of naloxone on vagally-induced acid secretion completely indicating that the action of naloxone depends on cholinergic background activity. Combined blockade of alpha- and beta-adrenergic receptors with phetolamine and propanolol reduced vagally-induced acid secretion in controls and during naloxone to a similar degree. Both adrenergic blocking agents also reduced the residual acid secretion observed during atropine or atropine + naloxone infusion. Measurements of plasma gastrin levels suggested that the naloxone-induced changes of acid secretion were not due to alterations of gastrin secretion. In summary these data demonstrate that vagally-induced acid secretion in anesthetized rats is largely due to cholinergic mechanisms with a small but separate contribution of adrenergic mechanisms. Endogenous opioids are activated during peripheral vagal stimulation attenuating vagally-induced acid secretion by modulation of cholinergic but not adrenergic mechanisms.

Effect of opioid active therapeutics on the ascending reflex pathway in the rat ileum.

For a long time therapeutic agents that interact with opioid receptors have been used in antidiarrheal therapy. The action of the opioid active substances on motility and transit have already been characterized; however, their effects on myenteric reflexes and their possible luminal action have not yet been investigated. Loperamide, fedotozine and beta-casomorphin-4, as well as the casomorphin-analogue beta-CM-4027, are, or have been, suggested as therapeutic agents and were studied in the isolated rat ileum for their effect on the ascending reflex pathway. beta-CM-4027 > fedotozine > loperamide > beta-casomorphin-4 caused a concentration-dependent inhibition of the ascending contractile reflex response with an IC(50)of 1.4x10(-7)M, 1.5x10(-6)M, 4.1x10(-6)M and 4.5x10(-6)M respectively. At the same time as the oral contractile reflex response was inhibited, all four opioid agonists (CM-4027 > beta-casomorphin-4 > fedotozine > loperamide) increased the latency of the reflex response. Both effects were blocked by naloxone, indicating the involvement of opioid receptors. These results demonstrate that opioid-active drugs and substances modify the peristaltic reflex by reducing the efficacy of the reflex response and modulating the timing of the reflex pathway. In a second series of experiments, luminal application of opioid-active drugs was compared with serosal application. beta-casomorphine-4 caused a concentration-dependent inhibition of the oral reflex response with an IC(50)of 3x10(-3)M which was 750 times higher than after serosal application. In contrast, a stable and highly selective kappa opioid agonist (U-50,488), which caused potent inhibition upon serosal application (IC(50): 2.3x10(-7)M), showed no inhibitory effect after luminal application up to a concentration of 10(-2)M. Thus casomorphins could have a local effect on the gut wall with no need for systemic absorption. This might be used for a possible therapeutic application.