enkephalin--leucine-2-alanine and Stomach-Ulcer

The article discusses treatment of 72 patients suffering from duodenal ulcer complicated by bleeding with the Soviet-made preparation Dalargin which is a synthetic analogue of leucine-enkephalin. The preparation was infused intravenously in a dose of 3 mg in physiological solution once daily. No other additional antiulcerative agents were give. The diagnosis was established on the basis of endoscopy. Dalargin led to cicatrization of the ulcers in 20.3 days in 60% of patient, obvious positive dynamics was noted in 32% of patients; in 8% of patients Dalargin proved ineffective. Basal hydrochloric acid secretion reduced by 56% during treatment.

Topics: Adult; Aged; Anti-Ulcer Agents; Clinical Trials as Topic; Duodenal Ulcer; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Humans; Middle Aged; Peptic Ulcer Hemorrhage; Stomach Ulcer; Wound Healing

We studied the effect of dalargin and its analogue [Dala]2-leu-enkephalin on the gastric mucosa in indomethacin-receiving animals. Indomethacin treatment was followed by severe injury to the gastric mucosa, decrease in proliferative activity of the epithelium, and stimulation of free-radical processes in gastric tissues. Dalargin significantly decreased the area of erosive and ulcerative lesions, had a normalizing effect on proliferation of epithelial cells, and reduced the degree of oxidative stress. Administration of [Dala]2-leu-enkephalin did not improve the state of the gastric mucosa.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Proliferation; DNA; Drug Interactions; Enkephalin, Leucine-2-Alanine; Epithelial Cells; Free Radicals; Gastric Mucosa; Gastrointestinal Agents; Indomethacin; Luminescence; Male; Oxidative Stress; Rats; Stomach Ulcer; Time Factors

Previously, using the acidified ethanol-induced ulcer model in rats, we demonstrated that the mainly vagus-dependent gastroprotective effect of intracerebroventricularly injected clonidine was mediated by beta-endorphin release in the lower brainstem. Presently, retroarcuate transections were used to evaluate the contribution of forebrain beta-endorphinergic projection in this mechanism. Since the transection trajectory affected the cingulate cortex and other forebrain structures, matching lesions were also performed. In control and sham-operated rats intracisternal injection of clonidine and the direct opioid receptor (delta type) stimulant peptide (D-Ala(2), D-Leu(5))-enkephalin caused a potent and fully naloxone-reversible (i.e. opioid receptor-mediated) protection against acidified ethanol-induced mucosal damage. In gyrus cinguli-transected rats (as well as in groups with midline hippocampal, thalamic and hypothalamic lesions) gastric mucosal protection induced centrally by direct delta-opioid receptor stimulation in the lower brainstem was completely abolished. The protective effect of clonidine was significantly reduced but it was still present in these animals. The residual protection by clonidine was naloxone-resistant, i.e. independent of an opioid mediation. Transections of the cingulate gyrus as well as thalamic but not the retroarcuate transections elevated plasma corticosterone levels. The changes seen in the clonidine/opioid-induced gastroprotection did not show any correlation with the changes in plasma corticosterone levels. It was concluded that (i) the transection of the cingulate cortex strongly influences the neural input to the nucleus tractus solitarii-dorsal motor vagal nucleus complex that is required for the activation of gastroprotective vagus outflow by delta-opioid receptor stimulation; (ii) the transection uncovers a direct, clonidine-induced gastroprotective pathway which is probably suppressed in intact animals.

Topics: Adrenalectomy; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenocorticotropic Hormone; Animals; Arcuate Nucleus of Hypothalamus; beta-Endorphin; Brain Stem; Cisterna Magna; Clonidine; Corticosterone; Enkephalin, Leucine-2-Alanine; Ethanol; Gyrus Cinguli; Hypothalamo-Hypophyseal System; Limbic System; Male; Microinjections; Rats; Rats, Wistar; Receptors, Opioid, delta; Solvents; Stomach Ulcer

This study evaluated the contribution of supraspinal opioid receptors to gastric mucosal protection in the rat. Intracerebroventricular (i.c.v.) and intracisternal (i.c.) injections of selective delta- [[D-Ala(2),D-Leu(5)]-enkephalin (DADLE), [D-Pen(2),D-Pen(5)]-enkephalin (DPDPE), deltorphin II], selective mu- [[D-Ala(2),Phe(4),Gly(5)-ol]-enkephalin (DAGO)] opioid receptor agonists and beta-endorphin (ligand of both receptor types) produced a dose-dependent inhibition of acidified ethanol-induced gastric mucosal damage. The ED(50) values for beta-endorphin, DAGO, DADLE, deltorphin II, and DPDPE were 3.5, 6.8, 75, 120, and 1100 pmol/rat, respectively, following i.c.v. and 0.8, 9.0, 45, 0.25, and 7 pmol/rat following i.c. injection. The gastroprotective effect of DADLE, deltorphin II, and DPDPE, but not that of DAGO, was inhibited by naltrindole, the selective delta-receptor antagonist. Since the delta(2)-receptor agonist deltorphin II was more potent than the delta(1)-receptor agonist DPDPE, the dominant role of central delta(2)-receptors in gastroprotection might be raised. The site of action for delta-receptor agonists is likely to be the brain stem since the peptides were more potent following i.c. than following i.c.v. administration. The gastroprotective effect was reduced following acute bilateral cervical vagotomy. Moreover, both the nitric-oxide synthase inhibitor N(G)-nitro-L-arginine (3 mg/kg i.v.) and the prostaglandin synthesis inhibitor indomethacin (20 mg/kg p.o.) decreased the protective effect of opioid peptides. The results indicate that 1) activation of supraspinal delta- and mu-opioid receptors induces gastric mucosal protection, 2) integrity of vagal nerve is necessary for the gastroprotective action of opioids, and 3) mucosal nitric oxide and prostaglandins may be involved in the opioid-induced gastroprotection.

Topics: Animals; beta-Endorphin; Brain; Capsaicin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalin, Leucine-2-Alanine; Enkephalins; Enzyme Inhibitors; Ethanol; Gastric Mucosa; Hydrochloric Acid; Male; Narcotic Antagonists; Oligopeptides; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, mu; Stomach Ulcer; Vagotomy

The function of the isolated perfused rat hearts was studied in four groups of experiments. Group 1--included the hearts of intact animals ("absolute control"), group 2--the hearts of rats subjected to 24 hour immobilization in supine position against the background of triple intramuscular injections of placebo (control), group 3 included the hearts of rats, which during 24 hour immobilization stress were thrice injected a synthetic analogue of endogenous opioids Dalargin in a dose of 3 g/kg, and group 4 included the hearts of animals, which during immobilization were administered Dalargin in a dose of 10 g/kg of body mass. Ulcer index as indicator of stress injury of gastric mucosa was also determined. In the control group of experiments (group 2) 24 hour immobilization stress resulted in complete depression of cardiac performance as compared with group 1, and ulcer index approximated 1. In group 3 the indices of cardiac performance even exceeded those in group 1 (intact animals). As compared with group 2, ulcer index in group 3 decreased by 9 times. In application of Dalargin in a dose of 10 g/kg complete preservation of heart function indices and complete prevention of stress injury of gastric mucosa were also observed. Thus, Dalargin possesses cardioprotective and anti-ulcerogenic effect in immobilization stress in rats. Most probably, this phenomenon can be attributed to its ability to inhibit the activity of sympathoadrenal system, which gets enhanced during stress.

Topics: Animals; Anti-Ulcer Agents; Enkephalin, Leucine-2-Alanine; Gastric Mucosa; Heart; Immobilization; In Vitro Techniques; Male; Rats; Rats, Inbred Strains; Stomach Ulcer; Stress, Physiological; Sympatholytics

Three series of experiments were performed in Wistar male rats. The first series covered the study of the function of isolated perfused hearts and the status of the gastric mucosa in intact animals. In series II and III, Stages IIIB-IV contact burn of 25% body surface was induced by a special device. The animals were observed for 24 hours. Following 23.5 hours of burn, the rats were injected placebo (Series II) or the synthetic Leu-enkephalin analogue dalargin, 10 micrograms/kg in the same amounts as placebo (Series III). After observation, the animals' hearts and stomachs were isolated and explored. In Series II, there was a considerable decrease in all the indices of cardiac function as compared to the controls, the ulcer index that characterizes the severity of stress-induced gastric mucosa injury was found to be 8.2. In Series III, the indices of cardiac function were even substantially higher than those in intact animals, the ulcer index was reduced to 0.01. Thus, dalargin, a Soviet synthetic Leu-enkephalin analogue, possesses marked anti-stress and cardioprotective effects in severe thermal trauma. The paper also considers the likely mechanisms responsible for the phenomena observed.

Topics: Animals; Burns; Disease Models, Animal; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Gastric Mucosa; Heart; Heart Failure; In Vitro Techniques; Male; Models, Cardiovascular; Rats; Rats, Inbred Strains; Stomach Ulcer; Stress, Physiological

Bilateral microinjections of the opiate antagonist naloxone (0.1, 1.0 and 10.0 micrograms) into the central nucleus of the amygdala (CEA) produced a significant potentiation of cold restraint-induced gastric pathology in rats. The opiate agonist, beta-endorphin (0.1, 1.0 and 10.0 micrograms), on the other hand, inhibited stress ulcer formation in a dose-related manner. Stress ulcer-attenuating effects were also seen with intra-CEA injections of the enkephalin analogs [D-Ala2,D-Leu5]enkephalin (10.0 micrograms) and [D-Ala2]Met-enkephalinamide (10.0 micrograms). Pretreatment of rats with naloxone (1.0 microgram) completely antagonized and even reversed the gastric cytoprotective effects of beta-endorphin (1.0 and 10.0 micrograms). The results indicate that the CEA is important in the gastric cytomodulatory effects of endogenous opiates during stressful experiences.

Topics: Amygdala; Animals; Endorphins; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Enkephalin, Methionine; Male; Microinjections; Naloxone; Rats; Rats, Inbred Strains; Receptors, Opioid; Restraint, Physical; Stomach Ulcer; Stress, Physiological

The role and possible clinical use of regulatory peptides, a new type of regulatory substances, is discussed. Special attention is paid to the opioid peptides and their analogues. The new drug dalargin has been developed on the basis of the endogenous opioid peptide leucine-encephalin. Its action has been studied using experimental models. It has been established that the optimal dose (10 micrograms/kg) of dalargin is effective in preventing ulceration in the cystamine duodenal ulcer rat model and the development of stomach erosive lesions in immobilization stress, reducing the degree of liver degeneration in CCl4 poisoning, etc. With an increase of the dose of dalargin the effect "escapes". Dalargin is primarily bound by delta-receptors, it produces no analgetic effect and does not enter the brain. Dalargin exhibits a pronounced cytoprotective and regeneratory action and may take an important place in treating the internal organ diseases.

Topics: Animals; Carbon Tetrachloride Poisoning; Cells, Cultured; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Duodenal Ulcer; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Hemorrhage; Humans; Lymphocytes; Mice; Necrosis; Pancreas; Rats; Receptors, Opioid; Stomach Ulcer