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P N Maton

Publications and source records attributed to P N Maton.

At least 19 recordsLinked to original sources
PubMed1998

The impact of gastroesophageal reflux disease on health-related quality of life.

BACKGROUND: Gastroesophageal reflux disease (GERD) affects health-related quality of life. METHODS: We enrolled 533 adults with a history of heartburn symptoms for at least 6 months of moderate to severe heartburn in 4 of the 7 days before study entry. Patients were treated with ranitidine 150 mg twice a day for 6 weeks and Gelusil antacid tablets as needed. We measured physician-rated symptoms and the Medical Outcomes Study short-form 36 (SF-36) Health Survey at baseline and after 6 weeks of treatment. Baseline results were compared with normative data for the US population and for patients with selected chronic diseases. Treatment response was defined as no episode of moderate to severe heartburn for 7 days. Statistical significance was set at P <0.001. RESULTS: GERD patients reported significantly worse scores on all 8 SF-36 scales, physical function and well-being, and emotional well-being compared with the general population. Patients with GERD reported worse emotional well-being than patients with diabetes or hypertension. Treatment responders demonstrated significantly less pain and better physical function, social function, vitality, and emotional well-being compared with nonresponders. CONCLUSIONS: Patients with GERD experience decrements in health-related quality of life compared with the general population. The impact of GERD is most striking on measures of pain, mental health, and social function. Successful treatment for GERD results in improvements in health-related quality of life.

Adult↗
PubMed1998

Meal type affects heartburn severity.

This study compared heartburn severity, number of episodes, and changes in esophageal pH induced by three meals. Symptomatic volunteers consumed the following on different occasions: McDonald's Quarter Pounder, french fries, and chocolate shake; McDonald's Sausage Biscuit with Egg, cheese, raw onion, and chocolate milk; and Wendy's Chili and red wine. Increases in reflux episodes over baseline for the hamburger, sausage biscuit, and chili meals were 28.8 +/- 5.7, 36 +/- 5.5 and 43.7 +/- 8.8, respectively. The sausage biscuit and chili increased reflux compared to the hamburger (P < 0.05), but the chili did not differ statistically from the sausage biscuit meal. Onset and peak heartburn for the hamburger, sausage biscuit, and chili meals were 45 and 90, 30 and 120, and 15 and 150 min, respectively. Despite lower fat content, chili and red wine promoted more reflux and heartburn pain than the other meals, demonstrating the importance of meal selection in provocative meal studies.

Cross-Over Studies↗
PubMed1997

Effects of oral rabeprazole on oesophageal and gastric pH in patients with gastro-oesophageal reflux disease.

BACKGROUND: This study examined the dose-response effects of the new proton-pump inhibitor rabeprazole on oesophageal and gastric pH in patients with gastro-oesophageal reflux disease. METHODS: This study had a single-centre, double-blind, randomized, two-way crossover design. Twenty patients were treated for two 7-day periods separated by a 7-10-day washout period. Patients were randomly assigned to receive either 20 mg of rabeprazole once daily during the first treatment period and 40 mg once daily during the second treatment period, or 40 mg during the first treatment period and 20 mg during the second treatment period. The primary efficacy variable was oesophageal acid exposure determined by 24-hour ambulatory pH monitoring. Acid-reflux time was defined as the percentage of time over 24 h that oesophageal pH was < 4. A dosage was considered effective if reflux time was reduced to < 6%, a number which has been our internal laboratory reference. RESULTS: Both rabeprazole 20 mg and 40 mg, given once daily, normalized reflux time, with decreases of 79% and 92% in acid exposure by day 7. Both dosages also decreased the mean total number of reflux episodes and the number of episodes lasting > 5 min, with no significant differences between dosages for any reflux parameter. Mean gastric pH increased with 20 mg from 1.86 at baseline to 3.71 on day 1 and 4.17 on day 7. Rabeprazole 40 mg once daily increased gastric pH from 2.01 to 4.37 on day 1, and to 4.65 on day 7. Safety analyses revealed no significant acute side-effects for either dosage. CONCLUSIONS: Pathological oesophageal acid exposure was normalized with both 20 mg and 40 mg dosages of rabeprazole, and the effects of these two doses did not differ. Rabeprazole was well-tolerated in this short-term study.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1996

Zollinger-Ellison syndrome. Recognition and management of acid hypersecretion.

Zollinger-Ellison syndrome (ZES) should be suspected if a patient has severe peptic ulceration, ulcers and kidney stones, a family history of ulcers or endocrine diseases, watery diarrhoea or malabsorption with or without ulcers, or if hypergastrinaemia is found. Any patient in whom ZES is suspected, and certainly if diagnosed, should be given large doses of antisecretory medication immediately. This should never be stopped except under controlled conditions or unless acid outputs have been reduced surgically. Patients cannot be managed safely without measuring acid outputs. These should be lowered to < 10 mmol/h, or < 5 mmol/h in patients with a previous gastric resection or severe oesophageal disease. Acid secretion can be controlled acutely in 70% of patients with an infusion of ranitidine 1 mg/kg/h, while 4 mg/kg/h will control acid in all. The initial oral dosage of omeprazole or lansoprazole should be 60 mg/day. Doses should then be adjusted daily on the basis of acid outputs. Proton pump inhibitors in a dosage of 60 mg/day will control acid output in most patients and 60 mg every 12 hours will control acid output in all. Doses can then often be slowly and progressively reduced. A parietal cell vagotomy reduces acid secretion and reduces, but does not abolish, the need for antisecretory medication. In patients with multiple endocrine neoplasia type 1 and hyperparathyroidism, a parathyroidectomy that results in normocalcaemia will reduce acid secretion and drug requirements. A total gastrectomy is rarely if ever needed nowadays. Given the high degree of safety of gastric antisecretory medications versus the risks of acid hypersecretion in patients with ZES, the mistakes in management of acid hypersecretion that must be avoided are those of giving insufficient medication and not measuring acid secretory rates.

Animals↗
PubMed1996

Irritable bowel syndrome: a study to investigate the mechanism(s) of visceral hypersensitivity.

Irritable bowel syndrome (IBS), is characterized by gastrointestinal hyperalgesia. In this study we investigated mucosal application of dyclonine on urge to defecate and pain threshold in volunteers and IBS patients (n = 10). Either saline or dyclonine (40 ml enema) was administered 10 minutes prior to rectosigmoid distension or cutaneous cold water pressor test. In IBS patients and volunteers no differences in cutaneous pain thresholds were noted. However, IBS patients had a lower pain threshold in the rectosigmoid than volunteers. In volunteers there was a significant difference between the threshold for urge to defecate and the threshold for rectosigmoid pain that was not apparent in IBS patients. Dyclonine administered directly into the rectosigmoid did not alter urge to defecate or pain threshold induced by distension in volunteers or IBS patients. These data suggest that the origin of pain perception is localized in deeper structures within the wall of the rectosigmoid colon.

Adult↗
PubMed1995

Pathophysiological effects of long-term acid suppression in man.

A critical evaluation has been made of the available evidence in man of the effects of prolonged low acid states on the structure and function of the stomach. Various human models have been examined. 1. Ageing does not affect acid output from the normal male stomach, and there may be an increase in women. With progressive atrophy of the corpus mucosa, which is more frequent and rapid in patients with gastric ulcer, there is an associated loss of secretory function. Chronic gastritis and atrophy are the most important age-related changes, which in many cultures are hypothesized to develop via a prior Helicobacter pylori-related gastritis. However, H. pylori colonization of the mucosa decreases with increasing grades of gastric atrophy probably because intestinal metaplasia provides a hostile environment. Atrophy and intestinal metaplasia are associated with precancerous lesions and gastric cancer. Apparent hyperplasia of the gastric argyrophil endocrine cells is a common and spontaneous phenomenon in patients with atrophic gastritis, which in part may be related to the preferential loss of nonendocrine cells. 2. Pernicious anemia is associated with a complete lack of acid production, marked hypergastrinemia, and endocrine cell hyperplasia in the majority of patients. ECL-cell carcinoids and gastric cancer occur with a prevalence of 3-7%, and endoscopic surveillance in routine clinical practice is not warranted. 3. Gastric ECL-cell carcinoids are rare events that have been described in association with two diseases in man, pernicious anemia and Zollinger-Ellison syndrome as part of multiple endocrine neoplasia syndrome type I, and usually relate to marked hypergastrinemia and the presence of chronic atrophic gastritis with gastric antibodies or a genetic defect rather than the presence or absence of acid. Regression or disappearance of ECL-cell carcinoids, either spontaneously or after removal of the gastrin drive, has been recorded. Lymph node, and rarely hepatic, metastases are documented but death in these cases has been anecdotal. 4. Therapy with H2 antagonists may result in up to a twofold rise in serum gastrin levels but in man no endocrine cell hyperplasia has been recorded. However, the data for H2 antagonists on these aspects are very limited. There is no drug-related risk of gastric or esophageal cancer, although the incidence of the latter may be raised. Long-term treatment with omeprazole is associated with a two- to fourfold increase in gastrin levels over baseline values in one third of patients and apparent endocrine cell hyperplasia in 7% of cases overall.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1995

Somatostatin receptor subtype 3 mediates the inhibitory action of somatostatin on gastric smooth muscle cells.

Previous functional studies show that somatostatin (SS) interacts with specific receptors to inhibit relaxation in gastric smooth muscle cells. There are no ligand binding studies, and it is unknown which of the five subtypes of SS receptors mediates the action. Dispersed gastric smooth muscle cells from guinea pig bound both 125I-labeled SS-14 and 125I-D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-Nal-NH2 (where Nal indicates N-naphthylalanine) (cyclo-SS-8), a synthetic peptidase-resistant octapeptide SS analogue. SS-28 and SS-14, cyclo-SS-8, and SS analogue D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol [SMS-(201-995) (octreotide)] inhibited 125I-cyclo-SS-8 binding with relative potencies of SS-28 = cyclo-SS-8 = SMS-(201-995) (octreotide), and the binding was not affected by the addition of protease inhibitors. SS-14 caused inhibition only in the presence of protease inhibitors. Ligand analysis demonstrated a two-binding-site model. Analysis of the relationship between biological function and binding suggested the high-affinity sites mediated the relaxant action of SS. 5'-Guanylylimidodiphosphate [Gpp-(NH)p] inhibited binding by reducing the affinity of the high-affinity site. Six SS-8 analogues that distinguish SS subtypes showed that 125I-SS-14 bound to somatostatin receptor subtype 3 (SSTR3). The results demonstrated that gastric smooth muscle cells possess distinct receptors for SS of the SSTR3 subtype. Occupation of these sites inhibits relaxation in gastric smooth muscle cells. Modulation between the high- and low- affinity binding states of SSTR3 is at least partially mediated by activation of guanine nucleotide regulatory proteins.

Animals↗
PubMed1994

Expanding uses of octreotide.

This chapter reviews the therapeutic use of octreotide in a variety of pancreatic disorders, including acute pancreatitis, in the prevention of postoperative and post-ERCP pancreatitis, in the control of postoperative pancreatic fistulae, and in chronic pancreatitis for the control of pain and of pseudocysts and ascites. The review also discusses the use of octreotide in intestinal disorders of motility, gastrointestinal bleeding, intestinal fistulae and refractory diarrhoea, including the diarrhoeas of AIDS, diabetes, short gut, chemotherapy, ileostomy and gastric surgery. The use of octreotide in neuroendocrine tumours, both for therapy and diagnostic imaging, is reviewed briefly. The paucity of adequately controlled studies in many of these situations is indicated and the potential usefulness of octreotide estimated.

Humans↗
PubMed1994

Management of Zollinger-Ellison syndrome.

Once the diagnosis of Zollinger-Ellison syndrome has been considered, it is important to ensure the safety of the patient by administering adequate antisecretory medication. There then ceases to be any urgency about the diagnostic work-up. It is essential to establish definitively that the patient has fasting hypergastrinemia and acid hypersecretion to establish the diagnosis of Zollinger-Ellison syndrome. The type of disease (i.e., sporadic or occurring as part of multiple endocrine neoplasia type I) should then be determined by assessment of endocrine function and anatomy because this will influence both the approach to control of acid secretion and the management of the tumor. Assessment of tumor extent and decisions about the management of the tumor can be delayed because these tumors are slow-growing. Because of the rarity of this syndrome, surgical aspects of the management of the disease are best undertaken in centers with particular expertise in this area.

Gastric Acid↗
PubMed1993

Prospective study of efficacy and safety of lansoprazole in Zollinger-Ellison syndrome.

Lansoprazole, a new substituted benzimidazole H+,K(+)-ATPase inhibitor, profoundly inhibits gastric acid secretion and has potential use in the management of diseases such as Zollinger-Ellison syndrome (ZES). In the present study we evaluated the efficacy and safety of lansoprazole in controlling acid hypersecretion in 20 patients with ZES. The starting dose was 60 mg once daily. Control of acid hypersecretion was defined as the dose required to reduce acid secretion to < 10 meq/hr in the last hour before the next dose. Doses were adjusted upwards until effective control was achieved. Patients not controlled with 120 mg once daily were placed on twice daily lansoprazole. Most patients (90%) required lansoprazole once daily. During long-term follow-up (mean 18.5 months), 25% of patients required upward dose adjustments and 25% of patients required twice daily lansoprazole. Following cessation of therapy, the mean time for gastric acid output to reach half basal acid output was 39.1 hr. Lansoprazole was well-tolerated without side effects. Clinical chemistry and hematological studies were unchanged, and no gastric carcinoids developed. These results demonstrate that lansoprazole is a safe and effective inhibitor of gastric acid hypersecretion in patients with Zollinger-Ellison syndrome. Because it has a long duration of action, lansoprazole can be used to control gastric acid hypersecretion in most patients with Zollinger-Ellison syndrome using a once daily dosing schedule.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1993

Omeprazole is superior to ranitidine plus metoclopramide in the short-term treatment of erosive oesophagitis.

Histamine H2-receptor antagonists are moderately effective in symptomatic treatment and healing of erosive oesophagitis, but they are not as effective as the proton pump inhibitor omeprazole. In some studies prokinetic agents seem to increase the effectiveness of H2-antagonists, but no study comparing the efficacy of omeprazole to H2-antagonists plus prokinetic agents has been performed. The purpose of this study was to compare the efficacy and tolerability of 20 mg omeprazole daily with 150 mg ranitidine b.d.s. plus the prokinetic agent 10 mg metoclopramide q.d.s. in patients with erosive oesophagitis. After both 4 and 8 weeks of treatment, omeprazole healed the mucosa in significantly more patients than did ranitidine plus metoclopramide. Omeprazole also provided significantly greater relief from daytime heartburn, nighttime heartburn, and acid regurgitation, and was associated with decreased concomitant antacid use. Although the overall incidence of adverse events was similar in the two treatment groups, a significantly higher number of treatment-related adverse events and more treatment-related withdrawals from the study occurred in the ranitidine plus metoclopramide treatment group. Omeprazole is more effective and better tolerated than the combination of standard dose ranitidine plus metoclopramide for patients with erosive oesophagitis.

Adult↗
PubMed1993

Review article: the management of Zollinger-Ellison syndrome.

Awareness of the sometimes subtle features of Zollinger-Ellison syndrome is important in order not to miss the diagnosis. Immediately after initial diagnostic tests, the patient should be given antisecretory medication, while tests for the type of Zollinger-Ellison syndrome and tumour extent can be delayed. Acid output should be decreased to < 10 mmol/h to control symptoms and prevent complications. Histamine H2-antagonists remain the best available intravenous therapy but omeprazole is the most effective long-term oral therapy and has proved to be safe in nearly 10 years of continuous use. The management of the gastrinoma has changed in recent years since the discovery that the majority of gastrinomas arise outside the pancreas. Exploratory surgery with tumour resection is the treatment of choice in sporadic Zollinger-Ellison syndrome but there are few indications for surgery in patients with Zollinger-Ellison syndrome and multiple endocrine neoplasia type-1. None of the available therapies for metastatic gastrinoma is very effective.

Diagnosis, Differential↗
PubMed1993

Neutral endopeptidase (EC 3.4.24.11) modulates the contractile effects of neuropeptides on muscle cells from the guinea-pig stomach.

The objectives of this investigation were to characterize neuropeptide-degrading enzymes on the surface of gastric muscle cells and to determine their physiological function. Neutral endopeptidase (NEP, EC 3.4.24.11) activity was measured using the fluorogenic substrate glutaryl-Ala-Ala-Phe-4-methoxy-2-naphthylamine. The NEP inhibitors phosphoramidon and DL-thiorphan (1 microM) inhibited degradation of the substrate by gastric muscle membranes by 100% and by freshly dispersed gastric muscle cells by 55-60%. The phosphoramidon or DL-thiorphan-inhibitable activity, attributed to NEP, of membranes was 112 +/- 4.0 pmol h-1 (micrograms protein)-1 and of cells was 4.2 +/- 0.8 nmol h-1 (10(6) cells)-1. This activity was associated with membranes prepared from cells and was not detected in the cytoplasm or in the cell incubation solution. Gastric muscle membranes were fractionated by electrophoresis and analysed by Western blotting using two NEP antisera. Both antisera recognized a protein in membranes with an electrophoretic mobility identical to that of recombinant human NEP and an apparent molecular mass of approximately 95 kDa. Neuropeptides were degraded by membranes with specific activities in the order of [Leu5]enkephalin > [Met5]enkephalin > gastrin-releasing peptide-10 (GRP-10) > [D-Ala2][Leu5]enkephalin > somatostatin-14. Phosphoramidon and DL-thiorphan similarly inhibited the degradation of GRP-10 (mean of 35% inhibition), somatostatin-14 (57%) and the aminopeptidase-resistant analogue, [D-Ala2][Leu5]enkephalin (75%). When aminopeptidases were inhibited with amastatin (10 microM) phosphoramidon inhibited degradation of [Leu5]enkephalin (54%) and [Met5]enkephalin (100%). Phosphoramidon increased the potency of the contractile effects of neuropeptides on muscle cells by > 280-fold for somatostatin-14, 17-fold for GRP-10, 18-fold for [Met5]enkephalin and 14-fold for [Leu5]enkephalin. The results show that an NEP-like enzyme on the surface of gastric muscle cells degrades and inactivates enkephalins, GRP-10 and somatostatin-14 and acts in a manner analogous to that of acetylcholinesterase in the neuromuscular junction of skeletal muscle.

2-Naphthylamine↗
PubMed1992

Effects of curative gastrinoma resection on gastric secretory function and antisecretory drug requirement in the Zollinger-Ellison syndrome.

The chronic hypergastrinemia in diseases such as the Zollinger-Ellison syndrome has trophic effects on the gastric mucosa, causing increased parietal cell mass reflected by increased maximal acid output (MAO) and basal acid output (BAO). The time course for the development of these gastric changes in humans is unknown, and controversy exists regarding whether reversal of the hypergastrinemia results in rapid normalization of gastric secretory function. To address these uncertainties, gastric secretory function was prospectively evaluated in 20 patients with the Zollinger-Ellison syndrome undergoing successful curative resection of gastrinoma. Each patient had gastric acid measurements, imaging studies, fasting serum gastrin and secretin provocative testing preoperatively, postoperatively at 3-6 months, and yearly thereafter. Preoperative mean BAO was 39 mEq/h, MAO 56 mEq/h, BAO-MAO ratio 0.73, and fasting gastrin output 1020 pg/mL. All patients were evaluated at 6 months, 17 at 1 year, 15 at 2 years, 13 at 3 years, and 9 at 4 years. By 3-6 months, MAO decreased by 50% in men (mean, 30 mEq/h) and by 35% in women (mean, 29 mEq/h) and then remained relatively unchanged for up to 4 years. Before surgery, 14 of 20 patients (70%) had an elevated MAO, whereas 4 years after resection, none of 9 patients had elevated levels. By 3-6 months, BAO decreased by 75% and remained unchanged for up to 4 years. At 3-6 months, 56% of patients were mild hypersecretors and 67% remained hypersecretors up to 4 years. Preoperatively, the BAO-MAO ratio was elevated in 16 of 20 patients (80%); postoperatively, only 5 of 18 patients (28%) at 3-6 months, 2 of 15 (13%) at 1 year, and 2 of 10 (20%) at 4 years continued to have elevated ratios. Preoperatively, the mean ranitidine dose was 1597 mg/day, whereas after surgery the mean dose was 535 mg/day at 3-6 months and approximately 300 mg/day at 1-4 years with 8 patients requiring no antisecretory drug. These results show that the trophic effects of chronic hypergastrinemia are, in general, rapidly reversible with a 50% decrease in MAO within 3-6 months of cure. Similarly, BAO decreased by 75% within 3-6 months. Despite these decreases, careful monitoring of acid secretion is required after reversal of the chronic hypergastrinemia in diseases such as the Zollinger-Ellison syndrome, because 55% of patients at 3-6 months and up to 67% at 4 years continue to remain mild hypersecretors and require low doses of antisecretory drugs.

Adult↗
PubMed1992

Zollinger-Ellison syndrome: technique, results, and complications of portal venous sampling.

All 95 portal venous sampling (PVS) procedures performed in patients with Zollinger-Ellison syndrome in the past 10 years at the authors' institution were reviewed. It was possible to catheterize at least one branch of the pancreaticoduodenal venous arcade in all but two procedures (98%). The highest concentration of gastrin was found in a selective sample from the pancreaticoduodenal venous arcade or the transverse pancreatic vein in 56 of 91 procedures (62%). Selective sampling of pancreatic head veins yielded a gastrin gradient sufficient for localization in 60 patients (63%). Among 55 solitary sporadic gastrinomas identified at surgery, PVS allowed correct localization of the tumor in 32 (58%); if selective samples had not been obtained, only eight (15%) would have been localized (P less than .0005). Sensitivity was the same for tumors in the gastrinoma triangle (64%) and the body or tail of the pancreas (60%). There were no false-positive results. The overall complication rate was 20%, but most complications were abdominal pain lasting 3 days or less. Six patients (6%) had serious complications.

Abdominal Pain↗
PubMed1992

Actions of somatostatins on gastric smooth muscle cells.

The effects of somatostatin-28, somatostatin-14, and a synthetic somatostatin octapeptide analogue, D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-Nal-NH2 (cyclo SS-8) were examined on contraction of dispersed gastric smooth muscle cells from guinea pigs. The somatostatins did not cause contraction of gastric smooth muscle cells, nor did they inhibit carbachol-stimulated contraction. However, they reversed vasoactive intestinal peptide (VIP)-induced inhibition (relaxation) of carbachol-stimulated contraction. Somatostatin-28 had a half-maximal effect (EC50) at 1.6 +/- 0.8 nM, cyclo SS-8 at 0.6 +/- 0.3 nM, but somatostatin-14 had no effect even when used in concentrations as high as 1 microM. Incubation of muscle cells with peptidase inhibitors phosphoramidon (1 microM) plus amastatin (10 microM) had no effect on the EC50 of somatostatin-28 or cyclo SS-8 but increased the potency of somatostatin-14 greater than 1,000-fold. When peptides were incubated with muscle cells and the products applied to high-performance liquid chromatography, cyclo SS-8 was not degraded, but somatostatin-14 was rapidly degraded when present alone, and the addition of peptidase inhibitors partially inhibited the degradation. Cyclo SS-8 had its maximal effect at 0.5-1 min and inhibited relaxation induced by VIP, isoproterenol, glucagon, or dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP). Cyclo SS-8 partially inhibited the increase in VIP-stimulated cAMP. Preincubation with pertussis toxin blocked the inhibitory action of cyclo SS-8 on VIP or DBcAMP-induced relaxation. These results indicate that gastric smooth muscle cells rapidly degrade somatostatin-14 and suggest that muscle cell peptidases could have a major effect on the actions of somatostatin-14.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1992

Characterization of opioid receptors on smooth muscle cells from guinea pig stomach.

On the basis of opioid-stimulated contraction of dispersed gastric smooth muscle cells it has been suggested that these cells possess opioid receptors of three subtypes: kappa (kappa), mu (mu), and delta (delta). We have used selective peptidase-resistant radioligands, agonists and antagonists, to examine receptor subtypes on dispersed gastric smooth muscle cells from guinea pigs prepared by collagenase digestion. The kappa-agonist U-50488H, the mu-agonist [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAGO), and the delta-agonist [D-Pen2,Pen5]enkephalin (DPDPE) each caused muscle contraction. The concentrations required to caused half-maximal contraction were U50488H (6 pM) greater than DAGO (13 pM) greater than DPDPE (6 nM). The abilities of these agonists to inhibit binding of [3H]U-69593 (kappa-preferring) by 50% were U50488H (43 nM) greater than DAGO (43 microM) greater than DPDPE (200 microM). Their abilities to inhibit binding of [3H]naloxone (mu-preferring) by 50% were DAGO (0.2 microM) greater than U50488H (10 microM) greater than DPDPE (greater than 100 microM). No binding could be detected with the delta-selective ligand [3H]DPDPE. The kappa-preferring antagonist Mr2266 (10 nM) preferentially inhibited contraction stimulated by the kappa-agonist U50488H, and naltrexone (10 nM) (mu-selective antagonist) preferentially inhibited contraction stimulated by the mu-agonist DAGO. ICI 174864 (200 microM; delta-selective antagonist) had no effect on contraction stimulated by mu-, kappa-, or delta-agonists. Contraction stimulated by the delta-agonist DPDPE was inhibited by both kappa- and mu-receptor antagonists. Studies on the effect of the antagonists on binding of [3H]naloxone and [3H]U69593 also provided evidence for kappa- and mu-sites but nor for delta-sites.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗