Gastric acid secretory responses to cholinergic and histaminergic stimulation in chronic morphine-treated rats.

The effects of chronic morphine administration on cholinergic and histaminergic activities were evaluated in rats by observing their gastric acid secretory responses to secretagogues. The responses of in-vivo perfused stomachs to 2-deoxy-D-glucose or pentagastrin, and of the isolated gastric mucosa to histamine or bethanechol, were not significantly different between naive and chronic morphine-treated animals. It is suggested that the chronic morphine-treated rats exhibit normal cholinergic and histaminergic activities as well as receptor sensitivities to acetylcholine and histamine.

Rapid induction of dependence to morphine in rats.

The rate of development of dependence to morphine was studied in female rats which were given increasing concentrations of morphine sulphate in their drinking fluid (5% sucrose solution). The occurrence of physical dependence was determined by the naloxone-precipitated withdrawal syndrome at various times during the 3-week experimental period. It was found that a significant degree of the withdrawal syndrome precipitated by naloxone was evident at 24 hr after starting administration of morphine; the syndrome reached its greatest intensity after the rats had received the opiate for 7 days. This study shows that dependence on morphine can be induced in rats by administration of the opiate in drinking fluid for a period shorter than 7 days.

Cardiovascular responses to sympathetic nerve stimulation in morphine-treated rats.

The effects of morphine on the responses of blood pressure and pulse rate to stimulation of sympathetic nerves or to intravenous administration of noradrenaline were studied in female rats which had been treated with either an increasing concentration of morphine sulphate in their drinking fluid (5% sucrose solution), or an acute intraperitoneal injection of morphine. Sympathetic nerve excitation was effected by electrical stimulation of the thoracic segments of the spinal cord in pithed rats. Both sympathetic nerve stimulation and noradrenaline produced dose-dependent changes in blood pressure and pulse rate in naive rats and in the sucrose-drinking controls. Animals which had been chronically treated with morphine in their drinking fluid for 21 days showed significantly less intense responses to sympathetic nerve stimulation. However, these decreased responses were not observed in rats given acute treatment with morphine. Chronic treatment with morphine did not significantly influence the changes in blood pressure or pulse rate induced by noradrenaline. These findings suggest that chronic treatment with morphine lessens the cardiovascular responses to stimulation of peripheral sympathetic nerves in rats. The mechanism is not clear, but it seems unlikely to be due to changes in the sensitivity, or perhaps the number, of adrenoceptors.

The inhibitory action of 5-hydroxytryptamine on gastric secretory function in rats.

The inhibitory action of 5-hydroxytryptamine (5-HT) on gastric function was studied in vagotomized rats. 5-HT (0.6, 1 or 5 mgkg-1, s.c.) dose-dependently reduced gastric acid secretion evoked by histamine, pentagastrin or methacholine. Pepsin secretion induced by pentagastrin or methacholine was also depressed by 5-HT. Basal secretion of both acid and pepsin was not significantly affected by any of the three 5-HT doses. Indomethacin pretreatment, which significantly decreased gastric mucosal prostaglandin E2 content, did not modify the inhibitory effects of 5-HT on histamine-induced acid secretion, nor did phentolamine or propranolol. This study suggests that 5-HT inhibits gastric secretory function through mechanisms other than by sympathetic influence or increased prostaglandin synthesis. The inhibitory action appears not to be vagus-dependent. Other mechanisms of action are discussed.

Arterial catecholamine levels in morphine-treated rats subjected to sympathetic nerve stimulation.

1. The effect of acute or chronic morphine treatment on the changes in arterial noradrenaline and adrenaline levels in response to sympathetic nerve stimulation was studied in rats. 2. Rats which had been chronically treated with morphine in their drinking fluid for 21 days were shown to be morphine-tolerant, as revealed by the tail-immersion test for analgesia. 3. It was found that animals given either acute or chronic morphine treatment had similar basal concentrations of arterial catecholamines to their controls. 4. Sympathetic nerve stimulation produced significant increases in arterial noradrenaline and adrenaline levels in both the control and morphine-treated animals. However, the degree of arterial noradrenaline elevation was significantly less in morphine-tolerant animals. 5. This phenomenon was not observed in acutely morphine-treated rats or at 2 weeks following opiate withdrawal in animals which had been treated previously with morphine for 3 weeks. 6. The findings suggest that chronic morphine treatment in rats not only leads to opiate tolerance but also reduces catecholamine release in response to sympathetic nerve stimulation.

Changes in preganglionic sympathetic nerve function following chronic morphine treatment in rats.

1. The effects of acute or chronic morphine treatment on the changes in blood pressure and pulse rate in response to ganglionic stimulation or blockade and to vagal stimulation, and of isolated atria to field stimulation or noradrenaline, were studied. 2. In pithed rats, intravenously injected hexamethonium significantly depressed the blood pressure responses to sympathetic nerve stimulation. The ganglionic blocking effects of hexamethonium were significantly greater in chronically morphine-treated rats, but were not significantly affected by acute morphine administration in naive animals. 3. Intravenous administration of nicotine dose-dependently increased blood pressure and pulse rate. The magnitudes of these changes were not significantly affected by acute or chronic morphine pretreatment. 4. Studies with rat isolated atrial preparations revealed that the changes in atrial contractile rate and force in response to noradrenaline or field stimulation were not influenced by either acute or chronic morphine treatment. 5. Cervical vagal stimulation produced voltage- or frequency-dependent decreases in pulse rate and blood pressure. The responses were not significantly affected by chronic morphine treatment. 6. These findings suggest that the site of the changes in sympathetic function following prolonged exposure to the opiate appears to be on the preganglionic nerve fibres.

The effect of zinc on anaphylaxis in vivo in the guinea-pig.

The protective effects of pretreatment with zinc sulphate aerosols against bronchoconstriction induced by egg albumen or histamine aerosols were assessed in sensitized or non-sensitized guinea-pigs respectively. Pretreatment with an adequate concentration of zinc sulphate aerosol significantly prolonged the time of onset of bronchoconstriction in sensitized guinea-pigs challenged with egg albumen, but did not appreciably alter the onset time of histamine-induced bronchoconstriction in non-sensitized animals. These findings suggest that zinc aerosols may be of prophylactic value against bronchoconstriction of allergic origin.

The protective effects of sulphasalazine against ethanol-induced gastric damage in rats.

1 The inhibitory action of sulphasalazine on ethanol-induced gastric damage was studied in rats. 2 Sulphasalazine (62.5 or 125 mg kg-1, s.c.) did not affect basal gastric acid secretion but increased pepsin output. 3 Ethanol (40% v/v, 10 ml kg-1, p.o.) produced severe gastric glandular mucosal damage and lessened the stomach emptying rate of resin pellets, but it increased the levels of prostaglandin E2 (PGE2)-like activity in the glandular mucosa. 4 Sulphasalazine markedly prevented ethanol-induced damage and significantly elevated gastric wall mucus levels both in basal conditions and in the presence of ethanol. 5 Sulphasalazine caused a small insignificant increase in mucosal PGE2 levels in both control and ethanol-treated rats. The drug significantly increased mucosal PGE2 levels in indomethacin-treated animals, but did not prevent indomethacin-induced mucosal damage. 6 Sulphapyridine but not 5-aminosalicylic acid, constituents of sulphasalazine, showed a similar antilesion action to the parent drug, and prevented gastric wall mucus depletion in ethanol-treated animals. 7 This study elucidates the protective effects of sulphasalazine against ethanol-induced gastric lesions. The antagonistic action appears to be mediated, at least partly, through the preservation of gastric wall mucus by sulphapyridine.

5-HT3 antagonists reduce morphine self-administration in rats.

1. The effects of the 5-HT3 receptor antagonists, ondansetron and tropisetron, on morphine consumption were studied in naive and morphine-dependent rats. 2. The administration of ondansetron (1 microgram kg-1, i.p. twice daily) 7 days prior to, and during a 21-day period of, morphine availability (increasing concentration from 0.1 to 0.4 mg ml-1) in 5% sucrose solution reduced opiate intake from the 9th day of morphine treatment. 3. The administration of ondansetron (0.1 microgram kg-1, i.p. twice daily) or tropisetron (0.1 microgram kg-1, i.p. twice daily) on the 14th day of the 21-day period of morphine treatment failed to reduce opiate consumption. Administration of the larger doses of tropisetron (1 microgram kg-1) or ondansetron (1 microgram kg-1) reduced morphine consumption. 4. After receiving 21 days of treatment with morphine alone or with the ondansetron or tropisetron regimens identified above, the sucrose solutions were substituted with tap water for 7 days. These detoxified rats were then allowed a free choice of sucrose or morphine for 10 days. Animals that had received concomitant treatment with ondansetron or tropisetron showed reduced morphine intake when compared with the controls treated with morphine only or with vehicle-treated controls. 5. The administration of cyproheptadine (100 or 250 micrograms kg-1, i.p. twice daily) on the 14th day of 21-day morphine treatment failed to modify morphine intake and also failed to influence the subsequent intake of the opiate in the free choice situation. 6. It is concluded that ondasetron and tropisetron can reduce morphine intake in both naive and morphine-dependent rats.

Prevention by the 5-HT3 receptor antagonist, ondansetron, of morphine-dependence and tolerance in the rat.

1. The effect of ondansetron, a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist, was studied in morphine-addicted rats. Morphine-dependence and tolerance, induced by drinking increasing concentrations of morphine sulphate in 5% sucrose solution for 3 weeks, were demonstrated by the naloxone-precipitated withdrawal syndrome and tail flick response to a thermal noxious stimulus (water at 50 degrees C), respectively. 2. Morphine-dependence, assessed by naloxone precipitated withdrawal, was undetectable by the 6th day, when the animals drank only tap water for 7 days after the 3-week induction period. 3. When detoxified rats were offered sucrose and morphine solutions for 10 days, the recurrence of opiate solution preference with relapse to dependence and tolerance was observed. 4. Giving ondansetron (0.1 or 1 microgram kg-1; i.p.; twice daily) on the 14th day of, or 7 days prior to, the 3-week induction period reduced dependence and tolerance seen during the 3-week morphine induction and the 10-day drinking preference periods. 5. 5-Hydroxytryptamine2 (5-HT2) receptor antagonism by cyproheptadine (100 or 250 micrograms kg-1; i.p.; twice daily) did not influence morphine-dependence and tolerance. 6. These findings suggest that ondansetron may be useful for treating opiate addiction and lowering the recidivism rate.

Information overload in the teaching of pharmacology.

Medical students are usually drawn from the best of students, but it is not unusual to see these brilliant students fail their exams or even dismissed from medical school because of poor academic performance. Information overload has been recognized as one of the major contributing factors to this problem. The situation is expected to get worse, with the ever-present technology-induced exponential growth in information. In discussing this issue, the authors echo the concerns of several experts regarding the content overload of medical school curricula, particularly in pharmacology. It is the increasing awareness of this problem that led the Association of American Medical Colleges and the General Medical Council of Britain to promote the concept of a core curriculum for each of the principal disciplines in medicine. Several medical schools have adopted the concept and also the problem-based learning approach, which focuses on ameliorating the complex problems associated with information growth in medical education. Based on the authors' experience as medical students, medical practitioners, and pharmacology teachers, they discuss the factors that contribute to information overload, from psychological and nonpsychological perspectives. Issues such as the design and structure of the curriculum, the quality of training and effectiveness of the teachers (clinically qualified vs. nonclinically qualified teachers), and the psychological preparedness of the students are discussed. The authors make suggestions for improvement.

Nicotine and gastric ulcers in stress.

Chronic nicotine treatment worsens stomach mucosal damage by cold (4 degrees C) and restraint (stress): it dose- and time-dependently intensifies stress-evoked gastric glandular ulceration, mast cell degranulation and motility. Nicotine 50 micrograms/ml drinking water, given ad libitum to female Sprague-Dawley rats for 10 days, increases the sensitivity of the isolated stomach strip to acetylcholine-induced contractions; atropine abolishes this action. The isolated anococcygeus muscle from nicotine-treated male rats shows increased sensitivity to noradrenaline-induced contractions, but not to those by acetylcholine. Hexamethonium or atropine pretreatment antagonises stress-induced gastric effects in nicotine-drinking rats. Muscarinic M1- and M2-, but not M3-, receptor block (by pirenzepine, AF-DX 116BS and HHSiD, respectively) inhibits stress ulcer formation in female rats. Although tobacco smoking has been reported to increase free radical formation, mucosal xanthine oxidase which initiates free radical formation is uninfluenced by nicotine; antagonising this enzyme (by allopurinol) or hydroxyl free radical scavenging (by dimethylsulfoxide) does not lessen the effect of nicotine on stress-evoked ulceration. The findings suggest that chronic nicotine treatment produces partial ganglionic blockade of the vagal nerve which leads to muscarinic receptor supersensitivity. This phenomenon contributes significantly to the ulcer-worsening mechanism; muscarinic M1- and M2-receptors appear to be involved. The gastric ulcer-aggravating effect of nicotine in stressed rats appears not to be due to increased free radical formation.

Adrenalectomy, but not vagotomy, reverses the worsening effect of Ca2+ blockers on ethanol-induced gastric lesions in rats.

This study examines the influence of the adrenals and of the vagus nerve on the lesion-worsening action of nitrendipine or verapamil on 75% ethanol-induced gastric mucosal damage in rats. Bilateral adrenalectomy antagonized ethanol lesion aggravation by nitrendipine or verapamil; instead, dose-related lesion reduction was seen. Dexamethasone treatment of adrenalectomized rats restored the lesion-enhancing effects of both Ca2+ channel blockers. Bilateral subdiaphragmatic vagotomy failed to abolish the adverse action of nitrendipine or verapamil on ethanol lesions. The findings suggest that the adrenal corticoids modulate the worsening effect of Ca2+ channel antagonists on ethanol-induced gastric damage; when the influence of the adrenal steroids is removed, these compounds become gastroprotective.

Chronic parenterally administered nicotine and stress- or ethanol-induced gastric mucosal damage in rats.

Mini-osmotic pumps containing solutions of either 0.9% NaCl (infused at the rate of 0.5 microliter/h) or nicotine (infused in doses of 0.224, 1.03 or 1.88 mg/kg per day) were implanted s.c. into rats 12 days before experimentation. The alkaloid increased solid food consumption, but fluid intake and average weight gain were similar among the animals given saline or nicotine. Chronic nicotine treatment dose dependently intensified cold (4 degrees C)-restraint stress-induced ulceration and increased mast cell degranulation. Oral administration of 40% ethanol to nicotine-treated animals also produced greater mucosal damage; mast cell degranulation by ethanol was significantly worsened after alkaloid treatment. These findings show that the stress ulcer-intensifying action of the alkaloid is mainly through a systemic mechanism. In the case of ethanol-evoked mucosal damage, in addition to a topical effect, stimulation of the stomach wall ganglia is likely to participate in the exaggerated post-vagal ulcerogenic responses as seen in stress.

A correlative study of the antiulcer effects of zinc sulphate in stressed rats.

The effects on zinc sulphate pretreatment of rats on stress-induced gastric ulcers and on changes in mast cell counts were studied and correlated with changes in gastric mucosal microcirculation. The effects on zinc sulphate on blood pressure responses and on growth were also examined. Stress (2 h restraint at 4 degrees C) produced marked glandular mucosal ulceration, lowered the stomach wall mast cell counts and increased the microcirculatory blood volume in the superficial glandular mucosa. Zinc sulphate (22, 44 or 88 mg/kg; injected i.p. 48 h before stress) reversed all these changes in a dose-related manner. Blood pressure responses to i.v. acetylcholine, adrenaline or histamine were unaffected and growth of the rats as observed for 7 days after injection was not impaired. On the basis of these findings the mechanism of the antiulcer action of zinc sulphate is the following: inhibition of the stress-induced release of vasoactive agents from gastric mast cells and thus prevention of the subsequent microciculatory changes known to produce mucosal ulceration. Interference with vascular responses through direct blockade or toxicity is unlikely.

The influence of cimetidine, a histamine H2-receptor antagonist, on the gastric effects of reserpine in rats.

The effects of graded doses of cimetidine on both resting and reserpine-evoked gastric acid secretion were examined in relation to their influence on reserpine-induced ulceration, mast cell degranulation and mucosal microcirculatory changes in rat stomachs. Cimetidine 10 mg/kg or above reduced resting or reserpine-provoked gastric acid secretion as well as rumenal and glandular ulceration. However, non-acid-inhibiting doses, 5 mg/kg or below, continued to prevent glandular ulceration. Reserpine-evoked gastric glandular mucosal mast cell degranulation was unaffected by both acid-inhibiting and non-acid-inhibiting doses of cimetidine which dose-dependently blocked the superficial glandular mucosal microcirculatory volume changes. These results suggest that cimetidine prevents reserpine-induced glandular ulceration largely by blocking the ulcerogenic effect of histamine H2-receptor-mediated mucosal microcirculatory congestion, in contrast to antagonising rumenal lesions through acid inhibition; they also support the idea tha reserpine may release histamine mainly from the glandular mucosal mast cells. The possibility of another antiulcer mechanism, due to cytoprotection, is discussed.

The effects of zinc sulphate on vagal-induced mast cell changes and ulcers in the rat stomach.

The effects of zinc sulphate pretreatment on the formation of gastric ulcers, changes in intragastric pressure and changes in the gastric mucosal mast cell count induced by electrical vagal stimulation were studied in anaesthetized rats. Vagal stimulation produced a high gastric glandular ulcer incidence and ulcer index, increased the intragastric pressure, and reduced the number of granulated mast cells in the gastric mucosa and submucosa. Pretreatment with zinc sulphate (22, 44 ot 88 mg/kg), injected i.p. 48 h beforehand, reversed the changes in these parameters in a dose-related manner. These observations suggest that the inhibitory effects of zinc sulphate on mucosal mast cell degranulation may account for its ability to antagonise vagal-induced gastric glandular ulceration. The mechanisms involved in the aetiology of this type of gastric ulcer are discussed in the light of these results.

Disodium cromoglycate: a novel gastric antiulcer agent?

The influence of oral pretreatment with disodium cromoglycate (2.5 or 5 mg/kg X 9 doses) on the 4-h gastric effects of i.p. injected reserpine (5 mg/kg) was examined in rats. Disodium cromoglycate markedly prevented reserpine-induced ulceration, mucosal mast cell degranulation and superficial mucosal microcirculatory changes in the glandular portion of the stomach wall. These interesting results points to the possibility that disodium cromoglycate may also have gastric antiulcer effects in man.

Cholinergic-mediated gastric mast cell degranulation with subsequent histamine H1-and H2-receptor activation in stress ulceration in rats.

The effects of atropine, mepyramine, metiamide or NaHCO3 on gastric ulceration, gastric secretion and gastric mast cell degranulation were studied in stressed pylorus-occluded rats. The influence of dexamethasone pretreatment on stress ulcers in animals without pylorus occlusion (intact rats) was also examined. Stress produced a high glandular lesion incidence and ulcer index, and markedly lowered gastric secretion and glandular wall mast cell counts. Injected 0.5 h before stress, atropine, mepyramine or metiamide strongly antagonised ulceration. Atropine or metiamide, but not mepyramine, reduced gastric secretion. Only atropine prevented stress-induced mast cell changes. NaHCO3, given intragastrically before stress, did not prevent ulceration or mast cell degranulation despite complete neutralisation of gastric acid. Dexamethasone-induced gastric mucosal mast cell depletion could reduce stress ulceration. The findings show that stress degranulates stomach mast cells via a cholinergic pathway; released histamine from this source is largely responsbile for gastric ulceration through H1- and H2-receptor effects. Histamine H2-receptor-mediated gastric acid may play only a small contributory role in stress ulcers in rats. The antiulcer mechanisms of histamine H1- and H2-receptor blockade are discussed.

Effects of stress and of autonomic blockers on gastric mucosal microcirculation in rats.

Changes in gastric mucosal microcirculation in rats were studied by using the method of intra-aortic injection of India ink, followed by microdissection of the mucosa. Acute stress, induced by restraint and exposure to cold for 2 hr, caused marked and significant vasodilatation in the gastric mucosa. This vasodilatation was prevented by pretreatment with atropine or chlorpromazine, but not by alpha- or theta-adrenoceptor blocking agents. Phentolamine caused significant vasoconstriction in the gastric mucosa of non-stressed rats, but when animals were stressed phentolamine induced a greater vasodilatation than was obtained with stress alone. These observations provide added support for the hypothesis that stress induces vagal overactivity, probably of central origin. The resulting strong contractions of the gastric wall, and compression of the intramural vessels, are probably responsible for degeneration of the mucosal cells leading to the formation of stress-induced ulcers in the rat.