beta-endorphin and Stomach-Ulcer

Beta-endorphin, deltorphin II, [D-Ala2, Phe4, Gly5-ol-enkephalin (DAGO) as well as endomorphin-1 and endomorphin-2 injected intracerebroventricularly (i.c.v.) induced gastroprotective action. It has been raised that endogenous opioids may have a central role in maintaining gastric mucosal integrity. Therefore we aimed to study the role of endogenous opioid system in the gastroprotective action induced by activation of alpha 2-adrenoceptors, nociceptin- and cannabinoid-receptors. Our results suggest that the non-selective opioid receptor antagonist naloxone (27 nmol i.c.v.) and the delta-opioid receptor antagonist naltrindole (5 nmol i.c.v.) abolished the mucosal protective effect of alpha 2-adrenoceptor agonists clonidine (470 pmol i.c.v.) and rilmenidine (45 pmol i.c.v.), nociceptin (1 nmol i.c.v.) and the cannabinoid receptor agonist anandamide (110 nmol i.c.v.). Based on our findings it can be raised that opioid system besides its well known regulatory functions might be involved in maintenance of gastric mucosal integrity.

Topics: Animals; Arachidonic Acids; beta-Endorphin; Clonidine; Endocannabinoids; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Ethanol; Excitatory Amino Acids; Gastric Mucosa; Injections, Intraventricular; Male; Naloxone; Naltrexone; Narcotic Antagonists; Neurotransmitter Agents; Nociceptin; Oligopeptides; Opioid Peptides; Oxazoles; Polyunsaturated Alkamides; Rats; Rats, Wistar; Receptors, Opioid; Rilmenidine; Stomach Ulcer

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 effects of water-immersion-induced stress and intraperitoneal (i.p.) administration of selected neuropeptides on the levels of thyrotropin-releasing hormone (TRH) and prostaglandin E2 (PGE2) were studied in the rat stomach. Water-immersion caused a significant decrease immunoreactive-TRH (ir-TRH) concentrations in the stomach, and a significant increase in ir-TRH concentrations in the gastric juice. The concentrations of PGE2 were significantly increased at 0.5-4 hrs, and significantly decreased at 6-8 hrs after water-immersion. In the experiment of i.p. administration of selected neuropeptides, the level of ir-TRH in the stomach was significantly decreased after VIP injection, whereas it was significantly increased after beta-endorphin injection. The concentration of PGE2 was significantly decreased in the stomach after i.p. administration of TRH and VIP. However, it did not change after beta-endorphin injection. These results indicate that some neuropeptides may participate in regulating the endogenous level of PGE2 and that these interrelations between neuropeptides and PGE2 may be important as ulcerogenic factors in stress ulcers induced by water-immersion in the rat.

Topics: Animals; beta-Endorphin; Dinoprostone; Gastric Juice; Gastric Mucosa; Immersion; Injections, Intraperitoneal; Male; Rats; Rats, Inbred Strains; Stomach Ulcer; Stress, Physiological; Thyrotropin-Releasing Hormone; Vasoactive Intestinal Peptide

In white rats with experimental ulcer of the stomach, a single session of acupuncture (AP) considerably increased the contents of beta-endorphine (ED) and adrenaline (A) in the hypothalamus. Repeated AP sessions aided to a progressive decrease in the ED, A and noradrenaline (NA) levels. The AP did not change essentially the dynamics of ED, A and NA by itself. The ulcer pathology against the background of AP sessions is accompanied by a change in activity of hypothalamic systems of the ED, A and NA, and by a formation of a specific neurochemical profile changing in time.

Topics: Acupuncture Points; Acupuncture Therapy; Animals; beta-Endorphin; Brain Chemistry; Epinephrine; Hypothalamus; Male; Norepinephrine; Rats; Stomach Ulcer; Time Factors

Neurotensin (NT) and bombesin, which are heterogeneously distributed in both brain and gastrointestinal tissue of several mammalian species, inhibit the formation of stress-induced gastric ulcers in rats. Many other endogeneous neuropeptides have also been reported to be present in brain and gastrointestinal tissue. The present study was conducted to evaluate the effect of some of these peptides on the development of cold-restraint stress (CRS)-induced gastric ulcers in rats. In addition, the effect of thyrotropin-releasing hormone (TRH), which antagonizes many of the CNS effects of NT, was investigated to determine whether this tripeptide antagonizes the cytoprotective effect of NT in this CRS model. All peptides were initially administered intracisternally (ic) in doses equimolar to 30 micrograms NT. As previously reported, NT (30 micrograms, ic) completely prevented the development of gastric ulcers in rats exposed to three hours of CRS. Bombesin, beta-endorphin, substance P, and somatostatin also exhibited cytoprotective activity. Several other peptides studied in the CRS model exerted no significant effects on the development of gastric ulcers; these included cholecystokinin octapeptide, gastrin, leu-enkephalin, met-enkephalin, and bradykinin. Two peptides, vasoactive intestinal polypeptide and TRH, significantly increased the severity of gastric ulcerations. The cytoprotective effect of NT was dose dependent. In contrast, lower doses of beta-endorphin, substance P, and somatostatin were cytoprotective whereas higher doses were not. Finally, concomitant ic injections of TRH antagonized the cytoprotective effects of NT and bombesin, but not that of beta-endorphin. The present results suggest that certain brain peptides may participate in modulating the gastric mucosal barrier, thereby increasing or decreasing its vulnerability to stress-induced lesions.

Topics: Animals; beta-Endorphin; Bombesin; Dose-Response Relationship, Drug; Endorphins; Male; Neurotensin; Peptides; Rats; Rats, Inbred Strains; Stomach Ulcer; Stress, Physiological; Thyrotropin-Releasing Hormone