Decreased pain inhibition in irritable bowel syndrome depends on altered descending modulation and higher-order brain processes.

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder involving abdominal pain and bowel dysfunction. IBS pain symptoms have been hypothesized to depend on peripheral and central mechanisms, but the pathophysiology is still unclear. The aim of the present study was to assess the contribution of cerebral and cerebrospinal processes to pain inhibition deficits in IBS. Fourteen female patients with diarrhea-predominant IBS (IBS-D) and 14 healthy female volunteers were recruited. Acute pain and the nociceptive withdrawal reflex (RIII reflex) were evoked by transcutaneous electrical stimulation of the right sural nerve with modulation by hetero-segmental counter-irritation produced by sustained cold pain applied on the left forearm. Psychological symptoms were assessed by questionnaires. Shock pain decreased significantly during counter-irritation in the controls (P<0.001) but not in IBS patients (P=0.52). Similarly, RIII-reflex amplitude declined during counter-irritation in the controls (P=0.009) but not in IBS patients (P=0.11). Furthermore, pain-related anxiety increased during counter-irritation in IBS patients (P=0.003) but not in the controls (P=0.74). Interestingly, across all subjects, counter-irritation analgesia was positively correlated with RIII-reflex inhibition (r=0.39, P=0.04) and negatively with pain-related anxiety (r=-0.61, P<0.001). In addition, individual differences in counter-irritation analgesia were predicted independently by the modulation of RIII responses (P=0.03) and by pain catastrophizing (P=0.01), with the latter mediating the effect of pain-related anxiety. In conclusion, these results demonstrate that pain inhibition deficits in female IBS-D patients depend on two potentially separable mechanisms reflecting: (1) altered descending modulation and (2) higher-order brain processes underlying regulation of pain and affect.

Mechanisms of hypersensitivity in IBS and functional disorders.

General introduction The concept of visceral hypersensitivity is accepted as being germane to several functional gastrointestinal disorders (FGIDs). The causes or risk factors associated with this hypersensitivity are unclear. This article addresses the proposed mechanisms leading to hypersensitivity: from genetic to inflammatory disorders, from central to peripheral alterations of function. However, in order to place visceral hypersensitivity in a more global perspective as an aetiological factor for FGIDs, it also provides a review of recent evidence regarding the role of other peripheral mechanisms (the intraluminal milieu), as also genetic factors in the pathophysiology of these disorders. The article has been divided into five independent sections. The first three sections summarize the evidence of visceral hypersensitivity as a biological marker of functional gut disorders, the peripheral and central mechanisms involved, and the role of inflammation on hypersensitivity. In opposition to visceral hypersensitivity as an isolated phenomenon in functional gut disorders, the last two sections focus on the importance of peripheral mechanisms, like motor disturbances, specifically those resulting on altered transport of intestinal gas, and alterations of the intraluminal milieu and genetics.

Ghrelin gastrokinetic action in patients with neurogenic gastroparesis.

Ghrelin has been shown to accelerate gastric emptying in animals where its effect appeared mediated through the vagus nerve. We aimed to verify the gastrokinetic capacity of ghrelin in human. Patients with gastroparesis attributed to a neural dysregulation by diabetes (n = 5) or surgical vagotomy (n = 1) were evaluated. The emptying of a test meal (420 kcal) was determined by the C13 octanoic acid breath test. Saline or synthetic ghrelin 1-4 microg/kg were given in 1 min bolus at the end of the meal. T-lag and T-1/2 were shorter during ghrelin than during saline administration [33 +/- 5 min versus 65 +/- 14 min (p < 0.01) and 119 +/- 6 min versus 173 +/- 38 min (p < 0.001)]. Ghrelin injection therefore accelerated gastric emptying of a meal in humans even in presence of a deficient gastric innervation.

Guidelines for the diagnosis and management of carcinoid tumours. Part 1: the gastrointestinal tract. A statement from a Canadian National Carcinoid Expert Group.

Carcinoid tumours are relatively rare and, in general, slow growing. They can be "non-functioning" tumours, presenting as a tumour mass, or "functioning" tumours secondary to the production of several biopeptides leading to the carcinoid syndrome. Though these tumours represent 0.25% of an oncology practice, a proper understanding of the clinical course of the disease and of the importance of appropriate diagnostic and therapeutic measures is very important. Proper patient management can lead to cure, particularly if the tumour can be fully resected, or to long-term palliation with medical treatment or cytoreductive surgery, or both, with significant prolongation of survival. A good understanding of the use of somatostatin analogues to achieve effective symptomatic control and of the importance of adequate follow-up and cardiac monitoring to prevent or effectively treat cardiac complications can contribute significantly to optimal control of this complex disease, ultimately improving the quality of life of affected patients. This article, developed by a group of Canadian experts, provides a framework that will assist clinicians in taking an optimal approach to managing their patients with carcinoid tumour.

Intolerance to visceral distension in functional dyspepsia or irritable bowel syndrome: an organ specific defect or a pan intestinal dysregulation?

Functional gastrointestinal disorders (FGID) are characterized by visceral hypersensitivity that could be specific to a region of the gut or reflect a diffuse pan-intestinal disorder. Sensory thresholds to distension at two visceral sites in patients with different FGIDs were determined. According to Rome II criteria, 30 patients from three groups were studied: patients with (i) functional dyspepsia (FD) or (ii) irritable bowel syndrome (IBS), and (iii) patients with concomitant symptoms of FD and IBS. Pain thresholds to balloon distension were determined in stomach and rectum. In FD patients, gastric intolerance to balloon distension was found in 91% patients; rectal hypersensitivity was documented in 18% patients. In IBS patients, rectal hypersensitivity was seen in 75% patients; while gastric hypersensitivity was never found. In patients with concomitant symptoms of FD + IBS, gastric and rectal intolerance to distension were present respectively in 82 and 91% patients. In the whole group, visceral intolerance to distension was documented at one site in 90% patients and at both sites, i.e. stomach and rectum, in 33% patients. Visceral intolerance to distension can be pan-intestinal in patients with multiple sites of symptoms, but appears organ-specific in patients exhibiting a specific site of symptoms.

Two new peptides to improve post-operative gastric ileus in dog.

Peptides can influence gastrointestinal motility, and from data obtained earlier in rats, we hypothesized that MTL-RP/Ghrelin, as well as CGRP receptor antagonist 8-37, could improve gastric post-operative ileus in dog. Dogs submitted to laparotomy were perfused with or saline or CGRP 8-37 or MTL-RP/Ghrelin on days 1-4 post-operatively while gastric emptying was estimated by measuring the postprandial increase in plasma acetaminophen ingested with a meal. As expected, in saline-treated animals the gastric emptying function was impaired post-operatively. The total amount of acetaminophen emptied (AUC over 150 min) on post-operative days 1-4 reached respectively 31+/-5%, 65+/-8%, 60+/-8% and 62+/-8% of the normal emptying capacity. CGRP antagonist increased the total emptying of acetaminophen to 52+/-5% on day 1, 95+/-2% on day 2 and 103+/-3% (P<0.05) on day 3. The delayed emptying of acetaminophen seen post-operatively in saline-treated animals could be completely reversed by MTL-RP/Ghrelin (P<0.01) whether it was given at 100 microg/kg on day 2 (102+/-7% of the normal emptying capacity), 4 microg/kg on day 3 (106+/-7%) or 20 microg/kg on day 4 (132+/-8%). As found earlier in rodents, CGRP receptor antagonist 8-37 as well as MTL-RP/Ghrelin are potent prokinetics to improve post-operative gastric ileus in dog.

Ghrelin/motilin-related peptide is a potent prokinetic to reverse gastric postoperative ileus in rat.

A novel peptide called ghrelin or motilin-related-peptide (MTLRP) was found in the stomach of various mammals. We studied its effect on the motor function of the rat gastrointestinal tract. In normal, conscious unoperated animals, ghrelin/MTLRP (5 or 20 microg/kg iv) significantly accelerated the gastric emptying of a methylcellulose liquid solution (gastric residue after 15 min: 57 +/- 7, 42 +/- 11, 17 +/- 4, and 9 +/- 3% of the ingested meal with doses of 0, 1, 5, and 20 microg/kg iv, respectively) Transit of the methylcellulose liquid solution was also accelerated by ghrelin/MTLRP in the small intestine but not in the colon. Des-[Gln(14)]ghrelin, also found in the mammalian stomach, was as potent as ghrelin in emptying the stomach (gastric residue after 15 min: 12 +/- 3% at a dose of 20 microg/kg iv). In rats in which postoperative gastrointestinal ileus had been experimentally induced, ghrelin/MTLRP (20 microg/kg iv) reversed the delayed gastric evacuation (gastric residue after 15 min: 28 +/- 7% of the ingested meal vs. 82 +/- 9% with saline). In comparison, the gastric ileus was not modified by high doses of motilin (77 +/- 7%) or erythromycin (82 +/- 6%) and was only partially improved by calcitonin gene-related peptide (CGRP) 8-37 antagonist (59 +/- 7%). Ghrelin/MTLRP, therefore, accelerates the gastric emptying and small intestinal transit of a liquid meal and is a strong prokinetic agent capable of reversing the postoperative gastric ileus in rat.

Pain hypersensitivity in patients with functional gastrointestinal disorders: a gastrointestinal-specific defect or a general systemic condition?

Visceral hypersensitivity was shown in patients with functional gastrointestinal disorders (FGID). The mechanisms underlying this sensory dysfunction remain undetermined. The initial hypothesis of a generalized reduction in pain tolerance was rejected by further studies that suggested a normal tolerance to somatic stimuli and led to the generally accepted assumption that pain intolerance is specific and exclusive for visceral stimuli in these patients. We wanted to revisit this theory by examining whether patients with FGID reported perception and tolerance to somatic pain differently from normal subjects and whether the response to somatic pain stimulus was correlated to gastrointestinal symptoms or psychological status or distress. Thirty-three patients with FGID (Rome II criteria)(F/M: 26/7; mean age 48+/-9.9) and 33 normal controls (F/M: 24/9; mean age 44.1+/-6.8) were asked to immerse their nondominant hand into 4 degrees C water for as long as possible (maximum 120 sec). Time before appearance of: (1) discomfort, (2) pain, and (3) withdrawing of the hand were noted. The intensity of pain was rated on a visual analog scale from 0 to 100. Self-report questionnaires were used to assess the severity of gastrointestinal symptoms (St-Luc GI index) and the psychological distress (SCL-90) in the patient group. Data are expressed in seconds as mean +/- SEM. Discomfort sensory thresholds were similar in controls and FGID patients (28+/-3 and 24+/-2, respectively; NS) whereas pain and withdrawing were significantly lower in FGID (41+/-3 and 76+/-6 sec) than in controls (62+/-6 and 102+/-4; P < 0.05). Pain intensity was similar in both groups (64+/-4 vs 67+/-3; NS). Female patients showed lower sensory thresholds than male patients and control females (pain thresholds: 39.8+/-3.4 vs 67.8+/-16.7 and vs 56.8+/-8.7; P < 0.05). Sensory thresholds were not different in subgroups of patients with FGID (irritable bowel syndrome and functional dyspepsia). No correlation was shown between sensory thresholds and gastrointestinal index or SCL 90-test. In conclusion, FGID patients showed a threshold to painful somatic stimulus that was lower than in normal subjects. These findings suggest that patients with FGID may have hyperalgesia and low pain tolerance that is not limited to the viscera, but that is part of a systemic general condition.

Identification of cDNA encoding motilin related peptide/ghrelin precursor from dog fundus.

A novel protein expressed by entero-endocrine cells of the mouse stomach was named prepromotilin Related Peptide (ppMTLRP) since it shares sequence similarities with the prepromotilin (Tomasetto et al.). The mouse ppMTLRP was found identical to the rat precursor of ghrelin (ppghrelin), an endogenous ligand specific for the Growth Hormone Secretagogue receptor identified from rat stomach (Kojima et al.). In the present study the cDNA encoding the dog counterpart of ppMTLRP/Ghrelin has been isolated and sequenced. The dog ppMTLRP/Ghrelin cDNA showed scores of respectively 80% and 75% homology with its human and mouse counterparts. By translation of the dog ppMTLRP/Ghrelin cDNA sequences, two ORFs could be deduced encoding either a 117 amino acid ppMTLRP/Ghrelin or the deleted Gln14 ppMTLRP/Ghrelin, as it was also known in mouse, rat and man. The dog ppMTLRP/Ghrelin shared 91% similarity and 78% identity, and 89% similarity and 78% identity with the human and mouse ppMTLRP/Ghrelin proteins respectively. The best score of homology was found in the MTLRP/Ghrelin sequence itself. Indeed the dog MTLRP/Ghrelin peptide shared 100% similarity and 93% identity, and 96% identity and similarity, with the human and mouse MTLRP/Ghrelin. Using Northern blot analysis to study dog ppMTLRP/Ghrelin gene expression on dog adult gut tissues, maximal expression level was found in the stomach fundus and corpus, and no expression could be detected in the stomach antrum nor in the duodenum, jejunum, ileum, colon or liver. In conclusion, we have identified ppMTLRP/Ghrelin from dog, and found that it is highly conserved with man, mouse or rat. The expression pattern along the gastro-intestinal tract is similar to the expression pattern previously described in mouse.

Oral pantoprazole for acid suppression in the treatment of patients with Zollinger-Ellison syndrome.

BACKGROUND: The management of patients with gastric acid hypersecretion due to gastrinoma, usually recognized as Zollinger-Ellison syndrome (ZES), was radically changed 10 years ago by the use of proton pump inhibitors. Surgical treatment now concentrates on tumour excision, and in the majority of patients, gastrectomy is no longer required to prevent complications of acid hypersecretion that can be managed pharmacologically. AIMS: To verify the ability of pantoprazole to control gastric acid hypersecretion and the clinical effects of acid hypersecretion in seven patients with documented ZES. METHODS: Pantoprazole was administered at an initial dose of 80 mg daily for seven days before basal acid output (BAO) was measured at 08:00, ie, 1 h before the next dose of pantoprazole was normally ingested. A lower (40 mg) or higher (120 mg or more) dose of pantoprazole was then used to keep the BAO in the therapeutic range (between 0.1 and 10 mmol/h) and to control clinical symptoms such as acid-related pain or diarrhea. RESULTS: BAO and clinical symptoms were controlled with pantoprazole 40 mg daily in one patient, 80 mg daily in two patients, 120 mg daily in three patients and 160 mg daily in one patient. CONCLUSIONS: Pantoprazole was able to control acid hypersecretion in ZES patients when administered in doses between 40 and 160 mg daily. An initial dose of 120 mg given before further titration of the drug regimen appears to be a reasonable therapeutic strategy.

Digestive motor effects and vascular actions of CGRP in dog are expressed by different receptor subtypes.

Calcitonin gene-related peptide (CGRP) is a 37 AA peptide localized in blood vessels and nerves of the GI tract. Activation of CGRP receptors (subtypes 1 or 2) usually induces vasodilation and/or muscle relaxation, but its effects in dog and on gastroduodenal motility are still unclear. This study looked for the effect of CGRP and the antagonist CGRP8-37, specific for CGRP type 1 receptor, 1) on GI motility (interdigestive and postprandial), and 2) on hemodynamy, in conscious dogs. During the interdigestive period, the infusion of CGRP1-37 (200 pmol/kg/h) or CGRP8-37 (2000 pmol/kg/h) did not modify the duration of the migrating motor complex nor the release nor the motor action of plasma motilin. The gastric emptying of a solid meal (15 g meat/kg) was reduced by the administration of CGRP1-37 (AUC: 2196 +/- 288.6 versus 3618 +/- 288.4 with saline or T12: 78 +/- 7.3 versus 50 +/- 4.3 min; P < 0.01) and this effect was reversed by the antagonist CGRP8-37. CGRP1-37 significantly (P < 0. 01) diminished arterial pressures (118 +/- 1.6/64 +/- 1.4 vs. 125 +/- 1.4/75 +/- 1.2 mmHg with saline) and accelerated the basal cardiac rhythm (110 +/- 1.4 versus 83 +/- 1.6 beats/min). However, CGRP8-37 failed to block the cardiovascular effects of CGRP1-37. In dog, CGRP could influence digestive motility by slowing the gastric emptying of a meal through an action on CGRP-1 receptors. Hemodynamic effects of CGRP were not blocked by CGRP8-37 and seem therefore mediated by CGRP-2 receptor subtype.

Neural and muscular receptors for motilin in the rabbit colon.

Motilin receptors were classically recognized in the gastroduodenal area, where they help to regulate interdigestive motility. More recently, motilin receptors were identified in the colon where their biologic significance remains unclear. We aimed here to characterize the motilin receptors of the rabbit colon. Distal colon and duodenum were obtained from sacrificed rabbits. Tissues homogenized by Polytron were submitted to differential centrifugation to obtain neural synaptosomes or smooth muscle plasma membranes enriched solutions. Motilin binding to these membranes was determined by the displacement of (125)I MOT by the native peptide MOT 1-22, or by peptide analogues MOT 1-12 [CH(2)NH](10-11) or GM-109 and by erythromycin derivative GM-611. Motilin binding capacity was maximum in colon nerves (49.5 +/- 6.5 fmol/mg protein vs. 19.9 +/- 2.5 in colon muscles or 9.4 +/- 2.8 and 6.6 +/- 1.2 in duodenal muscles and antral nerves respectively); all tissues expressed similar affinity for MOT 1-22, and the motilin agonist GM-611 bound equally to neural or muscle tissues from the rabbit colon; the synthetic antagonist MOT 1-12 [CH(2)NH](10-11) showed greater affinity for colon nerves than for colon muscles (plC50: 7.23 +/- 0.07 vs. 6.75 +/- 0.03). Similar results were obtained with the peptide antagonist GM-109; receptor affinity toward MOT 1-12 [CH(2)NH(10-11)] was always five times superior in neural tissues, whether they came from the colon or the antrum, than in muscle tissues, whether they were obtained from colon or from duodenum. Motilin receptors are found in very high concentration in nerves and in muscles from rabbit colon; specific motilin receptor subtypes are identified in nerves (N) and muscles (M) of the rabbit colon; N and M receptor subtypes seem independent of the organ location.

Motilin receptors in the human antrum.

Motilin is an intestinal peptide that stimulates contraction of gut smooth muscle. The motilin receptor has not been cloned yet, but motilin-receptor agonists appear to be potent prokinetic agents for the treatment of dysmotility disorders. The aim of this study was to determine neural or muscular localization of motilin receptors in human upper gastrointestinal tract and to investigate their pharmacological characteristics. The binding of (125)I-labeled motilin to tissue membranes prepared from human stomach and duodenum was studied; rabbit tissues were used for comparison. Solutions enriched in neural synaptosomes or in smooth muscle plasma membranes were obtained. Various motilin analogs were used to displace the motilin radioligand from the various tissue membranes. The highest concentration of human motilin receptors was found in the antrum, predominantly in the neural preparation. Human motilin receptors were sensitive to the NH(2)-terminal portion of the motilin molecule, but comparison with rabbit showed that both species had specific affinities for various motilin analogs [i.e., Mot-(1-9), Mot-(1-12), Mot-(1-12) (CH(2)NH)(10-11), and erythromycin]. Motilin receptors obtained from synaptosomes or muscular plasma membranes of human antrum expressed different affinity for two motilin-receptor agonists, Mot-(1-12) and Mot-(1-12) (CH(2)NH)(10-11), suggesting that they correspond to specific receptor subtypes. We conclude that human motilin receptors are located predominantly in nerves of the antral wall, are functionally (and probably structurally) different from those found in other species such as the rabbit, and express specific functional (and probably structural) characteristics dependent on their localization on antral nerves or muscles, suggesting the existence of specific receptor subtypes, potentially of significant physiological or pharmacological relevance.

Evaluation of gastric emptying function in clinical practice.

In this retrospective analysis, we compared different methods to evaluate gastric emptying function, aiming to improve the sensitivity and the clinical availability of our diagnostic testing. In the first study, we compared, in 72 patients clinically suspected of gastroparesis, the emptying of a meal containing two solid nutrients with different disintegration rates: 111In-labeled scrambled eggs and 99Tc-labeled liver cubes. Gastric emptying of 111In-labeled egg was delayed in 12 of our patients and the evacuation of the 99Tc-labeled liver was prolonged in 19 patients. The choice of the nutrient was not important for the identification of diabetic gastroparesis (43% vs 57%; NS), but it was determinant in the case of patients suspected of idiopathic gastroparesis (12% were positive with the egg and 25% with the liver; P < 0.05). In the second study, we compared two different diagnostic methods in 46 patients: a simple radiological detection of the gastric emptying of radiopaque pellets, and the scintigraphic emptying of a solid meal containing 99Tc-labeled liver cubes. Both tests correlated perfectly in 78% of our patients. In 15% of the population (six of these seven patients were diabetics suspected of gastroparesis) the scintigraphic method was normal, while the evacuation of radiopaque pellets was delayed. For clinical purposes, we therefore propose: (1) the scintigraphic method should use liver rather than egg as a radiolabeled tracer in order to improve the sensitivity of the test for detection of gastroparesis; and (2) the radiological detection of radiopaque markers is a reliable and convenient method for the detection of gastroparesis in clinical practice. It is possibly more sensitive than scintigraphy.

Regulation of motilin release: studies with ex vivo perfused canine jejunum.

The regulatory process of motilin release was studied in segments of canine jejunum isolated and perfused ex vivo. The secretion of motilin in the effluent venous system of the isolated intestine was measured by radioimmunoassay in response to various pharmacological agents injected intra-arterially. Muscarinie agonist and antagonist, respectively, increased and decreased the release of motilin. The stimulatory effect of carbachol was still documented after tetrodotoxin (10(-5) M) was injected in the system to block neural influence on M cells. Bombesin and morphine also increased the release of motilin. The effect of bombesin was still documented in the presence of atropine or tetrodotoxin, but the stimulatory morphine effect was blocked by atropine. Both phenylephrine and octreotide decreased the release of motilin stimulated by carbachol in a jejunal segment pretreated and denervated with tetrodotoxin. Therefore, a revised model for the regulation of motilin release from M cells of intestinal mucosa can now be proposed. Cholinergic and bombesin receptors are present on M cells to encode a stimulatory signal, whereas adrenergic and somatostatin receptors are responsible for inhibitory transmission. The stimulatory effect of morphine is mediated via a muscarinic transmitter.

Neural mediation of the motilin motor effect on the human antrum.

To elucidate the mode of action of motilin on the stimulation of human gastrointestinal motility, we studied the effect of exogenous motilin during muscarinic or serotoninergic pharmacological blockade. Manometric recording of the interdigestive antroduodenal motility was carried out in 27 healthy volunteers until the appearance of a spontaneous antral phase III. The tested blocker was then administered intravenously and was followed 30 min later by a 10-min infusion of synthetic human motilin (50 ng/kg). Motilin administered on a background of saline induced a premature phase III migrating from the antrum to the duodenum in every tested subject (n = 5). A low dose of atropine (5 micrograms.kg-1.h-1 for 90 min) inhibited the motilin effect in two of five subjects [not significant (NS)], whereas a high dose of atropine (15 micrograms/kg given in 30 min) blocked the motilin-induced premature antral phase III in all instances (n = 5, P < 0.01). Exogenous motilin given with low-dose ondanseton (8 mg given in 15 min followed by 1 mg/h for 90 min) or high-dose ondansetron (32 mg given in 30 min) was without effect in three of seven (NS) or in two of five (NS) subjects, respectively. During the administration of 15 micrograms/kg atropine, when exogenous motilin always failed to induce a premature antral phase III motor, a phase III-type activity was generated at the duodenum in four of five subjects. We conclude that the induction by motilin of phase III activity in human antrum is dependent on muscarinic mediation and that the contractile effect of motilin on human duodenum involves a noncholinergic mechanism, different therefore from the antral pathway.

Heterogeneity of motilin receptors in the gastrointestinal tract of the rabbit.

Motilin, a 22-amino acid peptide synthesized in endocrine cells of intestinal mucosa, stimulates GI smooth muscle contractility. To elucidate the mode of action of motilin, we attempted to determine whether motilin receptors are localized on nerve cells or on smooth muscle cells of the GI tract. Mucosa-free tissues from rabbit antrum and duodenum were homogenized separately with a Polytron prior to differential centrifugation to obtain synaptosome or plasma membrane-enriched fractions, as determined by the distribution of [3H]saxitoxin (SAX) binding (neural membranes) and 5' nucleotidase (5'N) activity (smooth muscle plasma membranes). Motilin binding was evaluated by the displacement of [125I]motilin by motilin (1-22) on the various membrane fractions. In the antrum, motilin binding was highly correlated with SAX binding (r = 0.81, p < 0.0005), and also significantly with 5'N activity (r = 0.54, p < 0.05). In the duodenum, motilin binding correlated significantly with 5'N activity (r = 0.67, p < 0.005), but not with SAX binding (r = -0.11, NS). Receptor affinity, for the motilin antagonist MOT(1-12)[CH2NH]10-11, for motilin(1-22), and for the motilin agonist erythromycin lactobionate was significantly (p < 0.001, p < 0.001, and p < 0.05, respectively) higher in SAX-enriched fractions from the antrum than in 5'N-enriched fractions from the duodenum. Therefore, in the rabbit: 1) motilin receptors appear to be predominantly located on nerve tissues in the antrum and restricted to smooth muscle cells in the duodenum, and 2) antral receptors and duodenal receptors displayed different pharmacological characteristics, probably corresponding to two specific and heterogeneous motilin receptor subtypes.

Structural effects of the selective reduction of amide carbonyl groups in motilin 1-12 as determined by nuclear magnetic resonance.

Motilin is a 22-residue peptide stimulating stomach and intestinal motility. The motilin 1-12 fragment displays biological effects similar to the native peptide. Selective reduction of the amide carbonyl groups to form CH2NH analogs leads to a significant reduction in activity for the first two N-terminal positions and to a complete loss of activity for all other positions. The structures of motilin 1-12 and ten reduced analogs were investigated using the temperature dependence of the amide NH chemical shifts. In all the analogs, the structure of the N-terminal region (residues 1-5) was different from the structure of motilin 1-12, which is characterized by hydrogen bonding between Phe1 and Ile4. The structure of the C-terminal region of analogs was similar to the structure of motilin 1-12 for the first two reduction positions only (1-2 and 2-3), indicating that the C-terminal portion of motilin 1-12 is more critical for biological activity. Complete structural characterizations of motilin 1-12, [CH2NH]1-2, and [CH2NH]4-5-motilin 1-12 were performed by two-dimensional NMR spectroscopy and molecular modeling. The structural features observed confirm the differences based on the temperature dependence of the amide NH chemical shifts. These results demonstrate that conservation of the amide bond rigidity is essential for the activity of non-hydrolyzable analogs.

Release of 5-ASA from Pentasa in patients with Crohn's disease of the small intestine.

BACKGROUND: Pentasa is a controlled-release tablet made from semipermeable microspheres and designed to continuously deliver therapeutic quantities of 5-ASA (5-aminosalicylic acid) throughout the gastrointestinal tract. Scintigraphic studies in healthy subjects have documented that 5-ASA release could occur in the small intestine. We tested here the disintegration of Pentasa in the digestive tract of nine patients with Crohn's disease of the small intestine. MATERIALS: Each patient was given, after breakfast, a 250 mg tablet of Pentasa containing samarium-153 oxide. For 8 h the progression of the isotope in the gastrointestinal tract was followed using gamma camera scintigraphy. Plasma measurement of 5-ASA and acetylated 5-ASA was used to verify the liberation and absorption of 5-ASA. RESULTS: The Pentasa tablet appeared completely dissolved in the stomach by 117 +/- 18 min. Samarium oxide was first detected in the small intestine 60 +/- 5 min after its ingestion; it reached the colon after 280 +/- 13 min and it was completely absent from the small intestine at 360 +/- 26 min. Plasma concentrations of 5-ASA started to rise after 67 +/- 7 min and were maximal at 222 +/- 25 min. CONCLUSION: In patients with Crohn's disease of the small intestine, Pentasa microgranules start releasing 5-ASA in the proximal small intestine, acting locally to exert its beneficial effect.

Gastric emptying of solid food in edentulous patients.

Whether mastication of food by teeth is a physiological contributor in the process of nutrient digestion remains a debatable issue. In this study we sought to determine whether mastication could influence the gastric emptying of solid food. In 8 edentulous patients, we measured the gastric emptying of a test meal ingested with or without their dental prostheses. Clinical dental evaluation and Helkimo chewing test were first performed to verify that the mastication deficiency was adequately corrected by the dental prostheses. A mixed meal containing ten cubes (1.5 cm) of beef liver labeled with 99mTc and mixed in a chicken stew was ingested by the subjects and followed by gamma camera external scintigraphy. The gastric emptying rate of the 99mTc-labeled liver was similar whether the meal was ingested with the denture properly inserted, allowing normal mastication of the liver cubes, or whether the food was swallowed unmasticated in the absence of functional prostheses (Tlag = 60 +/- 5 vs. 58 +/- 11 min, p = NS; T1/2 = 73 +/- 21 vs. 55 +/- 10 min, p = NS; Tlag+T1/2 = 133 +/- 19 vs. 114 +/- 17 min, p = NS). These results show that gastric trituration and emptying of solid food was not facilitated by prior mastication.