Dopaminergic compounds affect gastric secretion and response to experimental gastric mucosal injury. We showed previously that the novel dopamine D4 receptor antagonist, clozapine, significantly reduces gastric acid secretion and restraint stress-induced gastric lesions. Because the selectivity of clozapine for D4 receptors has recently been questioned, we tested the ability of a known D1 receptor blocker, SCH23390, to affect clozapine-induced reduction in gastric acid secretion. SCH23390 given i.p. or i.c.v., at doses that did not affect gastric acid secretion, significantly blocked the anti-secretory effect of clozapine, administered either peripherally or centrally. These data suggest that neither clozapine nor SCH23390 exhibit as high a degree of selectivity for the dopamine D4 and D1 receptor, respectively, as previously believed.

Several novel arylpiperazine serotonin 1(A) receptor agonists, developed as anxiolytics, have antisecretory and gastroprotective effects in rats, E4424 (2-}4-[4-(4-chloropyrazol-1-yl)butyl]-1-piperazinyl{pyrimidine; Lesopitron dihydrochloride), has potent anti-gastric secretory and antiulcer effects. Preliminary data indicated an enhancing effect of E4424 on gastric mucus that may underlie its gastroprotective actions. We therefore tested the effects of acute and chronic administration of E4424 and of a reference 5-HT1A receptor agonist, 8-OHDPAT [8-hydroxy-2-(di-n-propylamino)tetralin], on gastric mucus levels in rats subjected to cold-restraint stress, a procedure associated with depletion of gastric mucus and the development of mucosal injury. Acute oral administration of E4424 increased adherent mucus levels by 12%, 11%, and 13%, relative to controls. Chronic E4424 significantly increased gastric mucus relative to controls (69% increase). Acute oral treatment with 8-OHDPAT did not affect gastric mucus level. Acute intraperitoneal 8-OHDPAT slightly increased mucus levels. Chronic twice per day 8-OHDPAT did not affect mucus levels; however, chronic once per day treatment with 8-OHDPAT significantly elevated gastric mucus levels at the highest doses used. For E4424, there is a strong correlation between reduction of gastric mucosal injury and increase in gastric mucus level, suggesting that the action of E4424 on glandular mucus levels is an important mechanism underlying its gastroprotective effects.

1. A selective dopamine DA1 receptor agonist, SKF38393, reduced the severity of experimentally-induced gastritis in rats. 2. This is the first such demonstration with a dopamine DA1 receptor agonist. 3. When considered together with other reported actions of D1/DA1 receptor agonists, these data confirm a significant gastroprotective role for dopamine.

This chapter describes animal models of stress in pharmacology. It highlights that restraint or immobilization is perhaps the most frequently and widely used method of applying a stressor to laboratory animals. The first restraint technique, by Selye, involved tying the rat's legs together and wrapping the rat tightly in a towel. A large number of restraint procedures have been developed. The use of restraint as a stressor results in reliable, reproducible syndromes of both peripheral and central dysfunction and disease. A great deal of pharmacological evidence and drug screening has been accomplished using this technique. The chapter also discusses that cold as a stressor has generally been applied acutely and thus represents a reasonable model of short-term, acute exposure to a stressor. The extent to which acute exposure to cold in the laboratory is representative of human environmental stress, generally of a more chronic nature, is an issue which remains unresolved. Nonetheless, cold exposure, particularly when used in conjunction with other stressors, can be useful for the pharmacological study of stress responses and the factors that mediate them.

1. Central dopamine (DA) exhibits large and rapid responses to stress challenge, particularly in the mesolimbic DA tract and, to a lesser degree, in the mesocortical tract.2. Over the last few years, there has emerged an increasing role for peripheral DA, especially gastrointestinal DA, as a modulator of gastroduodenal injury consequent to stress exposure.3. Evidence has accumulated which strongly supports a role for DA as an endogenous gastroprotective element and it appears that the dopaminergic "brain-gut axis" is a critical determinant of gastroduodenal mucosal integrity in the stress-challenged gut.

Annals of the New York Academy of SciencesVolume 597, Issue 1 p. 43-50 Decreased Gastric Acid Output Following Neuropeptide Y Administration into the Lateral Cerebral Ventricle of Conscious Ratsa S. BRIAN PENNER, Corresponding Author S. BRIAN PENNER Departments of Medicine, University of Manitoba Winnipeg, Manitoba, Canada R3E 0W3 Departments of Pharmacology and Therapeutics, University of Manitoba Winnipeg, Manitoba, Canada R3E 0W3bAddress for correspondence: Dr. S. B. Penner, Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, 770 Bannatyne Avenue, Winnipeg, Manitoba, Canada R3E 0W3.Search for more papers by this authorDONALD D. SMYTH, DONALD D. SMYTH Departments of Medicine, University of Manitoba Winnipeg, Manitoba, Canada R3E 0W3 Departments of Pharmacology and Therapeutics, University of Manitoba Winnipeg, Manitoba, Canada R3E 0W3Search for more papers by this authorGARY B. GLAVIN, GARY B. GLAVIN Departments of Pharmacology and Therapeutics, University of Manitoba Winnipeg, Manitoba, Canada R3E 0W3 Surgery Faculty of Medicine, University of Manitoba Winnipeg, Manitoba, Canada R3E 0W3Search for more papers by this author S. BRIAN PENNER, Corresponding Author S. BRIAN PENNER Departments of Medicine, University of Manitoba Winnipeg, Manitoba, Canada R3E 0W3 Departments of Pharmacology and Therapeutics, University of Manitoba Winnipeg, Manitoba, Canada R3E 0W3bAddress for correspondence: Dr. S. B. Penner, Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, 770 Bannatyne Avenue, Winnipeg, Manitoba, Canada R3E 0W3.Search for more papers by this authorDONALD D. SMYTH, DONALD D. SMYTH Departments of Medicine, University of Manitoba Winnipeg, Manitoba, Canada R3E 0W3 Departments of Pharmacology and Therapeutics, University of Manitoba Winnipeg, Manitoba, Canada R3E 0W3Search for more papers by this authorGARY B. GLAVIN, GARY B. GLAVIN Departments of Pharmacology and Therapeutics, University of Manitoba Winnipeg, Manitoba, Canada R3E 0W3 Surgery Faculty of Medicine, University of Manitoba Winnipeg, Manitoba, Canada R3E 0W3Search for more papers by this author First published: July 1990 https://doi.org/10.1111/j.1749-6632.1990.tb16157.xCitations: 12 a This work was supported in part by a grant from the Kidney Foundation of Canada (B.P.) and the Medical Research Council of Canada (G.G.). D. D. S. is the recipient of a Canadian Heart Foundation Scholarship. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume597, Issue1Neurobiology of Stress UlcersJuly 1990Pages 43-50 RelatedInformation

Matkephamid, a delta opioid receptor agonist, blocked cold-restraint stress ulcers, reduced absolute ethanol-induced gastric ulcers and, at the lowest and highest doses examined, reduced basal gastric acid secretion in conscious rats, all to a significant degree. The dose effects on stress ulcer formation parallel those seen against maximal electroshock seizures and suggest that both central as well as peripheral delta opioid receptors mediate gastrointestinal responses to stress.

Dopamine is an important enteric neuromodulator. Herein we review the data that support a role for dopaminergic involvement in experimental duodenal and gastric ulceration; gastric, pancreatic, and duodenal secretion; gastrointestinal motility; and gastric and intestinal submucosal blood flow regulation. There also is support for a role for dopamine and dopamimetic agents in the treatment of certain experimental gastrointestinal diseases because some highly selective dopamine agonists are gastroprotective when given either parenterally or centrally. Based upon these observations, we suggest that dopamine is a key element of the "brain-gut axis" and represents a potentially important target for pharmacotherapeutic exploitation.

Marine poisoning results from the ingestion of marine animals that contain toxic substances and causes substantial illness in coastal regions. Three main clinical syndromes of marine poisoning have important neurological symptoms—ciguatera, tetrodotoxin poisoning, and paralytic shellfish poisoning. Ciguatera is the commonest syndrome of marine poisoning and is characterised by moderate to severe gastrointestinal effects (vomiting, diarrhoea, and abdominal cramps) and neurological effects (myalgia, paraesthesia, cold allodynia, and ataxia), but is rarely lethal. Tetrodotoxin poisoning and paralytic shellfish poisoning are less common but have a higher fatality rate than ciguatera. Mild gastrointestinal effects and a descending paralysis are characteristic of these types of poisoning. In severe poisoning, paralysis rapidly progresses to respiratory failure. Diagnosis of all types of marine poisoning is made from the circumstances of ingestion (type of fish and location) and the clinical effects. Because there are no antidotes, supportive care, including mechanical ventilation in patients with severe paralysis, is the mainstay of treatment.