Morphine reduces vagal-stimulated gastric acid secretion through a central action

The influence of morphine on gastric acid secretion stimulated by 2-deoxy-D-glucose or electrical vagal stimulation was studied in anaesthetised rats with perfused stomachs. It was found that changes in gastric acid output induced by electrical vagal stimulation were not noticeably affected, whereas those evoked by 2-deoxy-D-glucose were significantly suppressed by morphine pretreatment. The depressant effect of the opiate on the acid secretion stimulated by 2-deoxy-D-glucose was abolished by naloxone pretreatment. It is suggested that morphine inhibits vagal-stimulated gastric acid secretion in rats by acting predominantly on opioid receptors in the central nervous system.     

Effects of tissue cultured ginseng on gastric secretion and pepsin activity]

Effects of the tissue cultured and cultivated ginseng on gastric secretion and pepsin activity were investigated. Fifty percent ethanol extracts of both cultured and cultivated ginsengs reduced gastric secretion and acid output in pylorus-ligated rats. They did not affect pepsin activity. The tissue cultured ginseng inhibited histamine and pentagastrin-induced acid secretion in rats, whereas the cultivated ginseng showed no such effect. They also suppressed acid secretion induced by 2-deoxy-D-glucose and baclofen [beta-(p-chlorophenyl)-gamma-aminobutyric acid], which are known to stimulate gastric acid secretion via the central nervous system. However, they had no effect on acid secretion induced by vagal stimulation. These results suggest that both tissue cultured and cultivated ginsengs may have an inhibitory effect on gastric secretion. The effect seems to be due to the inhibition of acid secretion via the central nervous system.     

C-type natriuretic peptide applied to the brain enhances exocrine pancreatic secretion through a vagal pathway

C-type natriuretic peptide (CNP) is the major natriuretic peptide in the brain and its mRNA has been reported in the central nervous system, which supports local synthesis and its role as a neuromodulator. The aim of the present work was to study the effect of centrally applied CNP on pancreatic secretion. Rats were fitted with a lateral cerebroventricular cannula one-week before secretion studies. The central administration of CNP dose-dependently enhanced pancreatic fluid and protein output. CNP response was diminished by atropine and hexamethonium, but it was abolished by vagotomy. Neither adrenergic antagonists nor the administration of (D-p-Cl-Phe(6),Leu(17))-vasoactive intestinal peptide (VIP antagonist) or N(omega) Nitro-L arginine methyl ester (L-NAME) (nitric oxide synthase inhibitor) affected CNP response. The effect induced by CNP was mimicked by 8-Br-cGMP but not by c-ANP-(4-23) amide (selective agonist of the natriuretic peptide receptor C). Furthermore, CNP interacted with cholecystokinin (CCK) and secretin in the brain to modify pancreatic secretion. Present findings show that centrally applied CNP enhanced pancreatic secretion through a vagal pathway and suggest that CNP response is mediated by the activation of natriuretic peptide guanylyl cyclase coupled receptors in the brain.     

Etorphine inhibition of pancreatic exocrine secretion in rats: comparison with methadone

The effects of etorphine, a potent opiate agonist without preferential affinity for mu, delta or kappa receptors, on exocrine pancreatic secretion were studied in rats fitted with chronic or acute pancreatic fistulas and compared to those of methadone, a well-documented mu agonist. In conscious rats etorphine (3 micrograms/kg s.c.) inhibited basal pancreatic secretion by about 50% for volume and bicarbonate output and by 70% for protein output. Pancreatic secretion returned to its basal level within 2 h. Methadone (5 mg/kg s.c.) was about equipotent but the inhibition lasted longer. The effects of both etorphine and methadone were completely antagonized by naloxone (1 mg/kg s.c.) and to a lesser extent by diprenorphine (10 microgram/kg s.c.). Yohimbine did not suppress the inhibitory effect of etorphine on protein output but showed some antagonism against the effects of etorphine on water and bicarbonate output. In anaesthetized rats etorphine (3 micrograms/kg) inhibited the pancreatic secretion stimulated by 2-deoxy glucose, a centrally acting vagal stimulatory agent, by 50-60% for volume and bicarbonate output and totally for protein output. The same dose of etorphine did not inhibit the pancreatic secretion evoked by vagal electrical stimulation, a peripheral stimulus. Methadone (5 mg/kg) inhibited the pancreatic secretion stimulated by 2-deoxy glucose to the same extent, but for a longer time than etorphine, and at the same dose did not suppress the pancreatic pancreatic response to vagal electrical stimulation. The inhibitory effects of etorphine and methadone in anaesthetized rats were completely suppressed by naloxone (1 mg/kg s.c.) and only reduced by diprenorphine (10 micrograms/kg s.c.).(ABSTRACT TRUNCATED AT 250 WORDS)     

Gastric acid inhibitory action of a GABA-related compound, 3-amino-3-phenylpropionic acid, in the rat

The acid inhibitory properties of 3-amino-3-phenylpropionic acid, a structural GABA analogue, were studied in the perfused rat stomach preparation. 3-Amino-3-phenylpropionic acid, 10 and 30 mg/kg i.v., dose dependently suppressed the gastric acid secretion induced by baclofen (2 mg/kg s.c.). This secretagogue action had been shown to be unaffected by either GABAA or GABAB receptor antagonists. The i.v. administration of 3-amino-3-phenylpropionic acid (3 and 10 mg/kg) was also effective to abolish the acid stimulatory effects of muscimol (1 mg/kg i.v.) and 2-deoxy-D-glucose (200 mg/kg i.v.). 3-Amino-3-phenylpropionic acid, even at the high dose (30 mg/kg i.v.) had no influence on the acid output in response to histamine and bethanechol. Furthermore, 3-amino-3-phenylpropionic acid had no significant effect on the acid secretion induced by electrical vagal stimulation. These results indicate that the antisecretory effect of 3-amino-3-phenylpropionic acid is different from those of antimuscarinics, H2-receptor antagonists and vagal blockade. Together, the results suggest that 3-amino-3-phenylpropionic acid might act in the brain to inhibit central regulation mechanisms of gastric acid secretion, probably through GABA mechanisms.     

Loperamide-induced inhibition of pancreatic secretion in rats

The effects of loperamide on exocrine pancreatic secretion were studied in rats fitted with chronic or acute fistulas. Intraduodenal injection of loperamide in conscious rats resulted in a dose-dependent inhibition of basal pancreatic secretion involving volume and bicarbonate and protein output with an ED50 of about 0.5 mg/kg. The maximal inhibition observed was about 60% for volume and bicarbonate output and 90% for protein output. Loperamide induced an inhibition of pancreatic secretion in conscious rats that was naloxone-sensitive and persisted in cimetidine-treated rats. Thus, it did not depend on modifications of gastric secretion. In anaesthetized rats, loperamide did not inhibit the pancreatic secretion evoked by agents acting directly on the pancreatic cells (acetylcholine, secretin, CCK) but it inhibited by 100% the pancreatic secretion induced by vagal electrical stimulation (VES) and by 80-100% that induced by 5 thio-glucose, a centrally acting vagal stimulatory agent. Loperamide inhibition of VES-induced pancreatic secretion was different from that obtained with morphine or methadone since these opiate drugs could only inhibit by 50-60% maximally the VES-stimulated pancreatic secretion. The loperamide inhibition of VES-induced secretion was naloxone-insensitive, while loperamide inhibition of 5 thio-glucose-induced secretion was in part naloxone-sensitive. These results suggest that loperamide exerts a potent inhibition of pancreatic secretion by acting on the nerve supply to the pancreas through both opiate and non-opiate mechanisms.     

Methadone inhibition of vagally induced pancreatic and gastric secretions in rats: Central and peripheral sites of action

Pancreatic and gastric secretions after stimulation with acetylcholine, electrical vagal stimulation or 2-deoxyglucose injection were studied in anestherized rats. The effects of methadone on these secretions were investigated. Maximal stimulation of pancreatic secretion by acetylcholine was not affected by methadone. Gastric acid stimulation by acetylcholine was only slightly decreased by methadone (30% or less). Electrical vagal stimulation of pancreatic and gastric secretions was progressively and dose-dependently decreased to a maximum of 50% by methadone. Maximal stimulation of pancreatic and gastric secretions by 2-deoxyglucose was completely suppressed by methadone with an ID₅₀ of about 1 mg/kg and an ID₁₀₀ of about 2.5 mg/kg for both secretions. It is concluded that methadone inhibits vagal stimulation of digestive secretions by acting both centrally and peripherally (probably by inhibiting the release of acetylcholine from vagal fibers). The central mechanism appears to be more important, since it occurs with lower doses and can produce complete suppression of secretion.     

Effects of intracerebroventricularly applied nicotine on enhanced gastric acid secretion and mucosal blood flow in rats

The effects of intracerebroventricularly administered nicotine on the elevated levels of gastric acid output and mucosal blood flow (MBF) were examined in anesthetized rats. Intravenous administration of both 2-deoxy-D-glucose (2-DG) and pentagastrin induced marked increases in gastric function and the intraventricularly applied nicotine diminished the increases induced by 2-DG but not those due to pentagastrin. This effect of nicotine was inhibited when hexamethonium was given concomitantly. In reserpinized rats, this inhibitory effect of nicotine on the 2-DG-induced increases in gastric function was abolished. Electrical stimulation of the lateral hypothalamic area induced increases in gastric function and these increases were also inhibited by intraventricularly administered nicotine. These results indicate that centrally administered nicotine has an inhibitory effect on both acid secretion and MBF, when these gastric parameters are maintained at relatively higher levels by central activation. Central noradrenergic inhibitory mechanisms in the regulation of gastric function may relate to the inhibitory effects of nicotine.     

Comparative effects of various centrally acting gastric secretagogues including PCPGABA and TRH in the perfused rat stomach preparation

The effects of 2-(p-chlorophenyl)-GABA (PCPGABA), thyrotropin releasing hormone (TRH), insulin and 2-deoxy-D-glucose (2DG) on gastric acid secretion, vagal nerve efferent activity and blood glucose level were examined in anesthetized rats. The latencies of onset of hypersecretion were 10 min for TRH (1 microgram/rat, i.c.), 20 min for PCPGABA (4 mg/kg, s.c.), 60 min for 2DG (200 mg/kg, i.v.) and 90 min for insulin (2 U/kg, i.v.), respectively. The secretagogue actions of PCPGABA and TRH were more potent than those of 2DG and insulin. All these secretagogues caused the efferent activation of the cervical vagal transmission, and the latencies for these vagal activation were shorter than those seen in gastric acid hypersecretion. Atropine and vagotomy completely abolished the secretagogue actions of these stimulants. PCPGABA and TRH were ineffective on the blood glucose level, unlike insulin and 2DG. These results suggest that PCPGABA, TRH, 2DG and insulin stimulate gastric acid secretion via central vagal cholinergic pathways, even though the precise mechanisms for each stimulant seem to be different.     

Effect of modafinil on pancreatic exocrine secretion in the rat. A comparison with methadone.

Modafinil is a recently developed drug which increases wakefulness in several animal species and in man, an effect involving, at least in part, central adrenoceptors. In the present experiments, the effect of modafinil was studied on a model of neurally stimulated secretion, pancreatic secretion induced by 2-deoxyglucose (2DG) in the rat, and compared with that of the mu-opiate methadone. Modafinil induced a dose-related inhibition of 2DG-stimulated pancreatic secretion, reaching more than 80% after 250 mg/kg i.p. The modafinil effect was suppressed by idazoxan or by large doses of prazosin but not by naloxone. In addition modafinil (250 mg/kg i.p.) did not change the pancreatic response to electrical vagal stimulation. Methadone also potently suppressed 2DG-stimulated pancreatic secretion, but in contrast to modafinil, the methadone effect was blocked by naloxone, but not by the adrenoceptor antagonists idazoxan, prazosin and propranolol. It is concluded that modafinil decreases centrally 2DG-stimulated pancreatic secretion through a pathway involving alpha 1- and alpha 2-adrenoceptors, without an interaction with opiate receptors.     

Phaclofen-sensitive GABA-B receptors do not mediate excitatory effects of baclofen on gastric secretion.

The present study investigates the effects of centrally or peripherally administered baclofen on gastric acid secretion from pylorus-ligated rats. The influence of baclofen on basal acid secretion from isolated guinea-pig gastric fundus was also evaluated. At all doses employed, intracerebroventricular baclofen significantly decreased acid secretion, this inhibitory action being antagonized by intracerebroventricular phaclofen. Intravenous baclofen induced both gastric inhibitory and excitatory responses at low and high doses, respectively. Intracerebroventricular phaclofen prevented the inhibitory effect, while neither intracerebroventricular nor intravenous phaclofen modified the stimulant action of parenteral baclofen. Both central and parenteral muscimol did not influence gastric acid secretion. Moreover, baclofen or muscimol were without effect on basal acid secretion from isolated guinea-pig gastric fundus, whereas bethanechol caused a marked and concentration-dependent stimulant action. The present results provide further evidence for the inhibitory role of central phaclofen-sensitive GABA-B receptors in the regulation of acid secretion. In addition they indicate that the hypersecretory effect exerted by parenteral baclofen may depend upon the activation of putative peripheral non-A and phaclofen-insensitive GABA-B receptors. Finally, peripheral GABA receptors do not appear to be significantly involved in the direct control of gastric secretion.     

Effect of mitragynine,derived from Thai folk medicine,on gastric acid secretion through opioid receptor in anesthetized rats

Mitragynine, an indole alkaloid from Thai folk medicine Mitragyna speciosa, exerts agonistic effects on opioid receptors. Gastric acid secretion is proposed to be regulated by opioid receptors in the central nervous system (CNS). Previously, we reported the dual roles (inhibition via micro-opioid receptors and stimulation via kappa-opioid receptors) of the opioid system in the central control of gastric acid secretion. We investigated whether mitragynine affects gastric acid secretion via opioid receptors in the CNS. Injection of mitragynine (30 microg) alone into the lateral cerebroventricle did not have a significant effect on basal gastric acid secretion in the perfused stomach of anesthetized rats. Injection of mitragynine (3-30 microg) into the fourth cerebroventricle, like morphine, inhibited 2-deoxy-D-glucose-stimulated gastric acid secretion. The inhibitory effect of mitragynine (30 microg) was reversed by naloxone (100 microg). These results suggest that mitragynine has a morphine-like action on gastric acid secretion in the CNS.     

Inhibitory effect of intravenous GABA antagonists on gastric acid secretion stimulated by secretagogues in rats

Effect of intravenous administration of GABA antagonists on gastric acid secretion in perfused stomachs was studied in rats anesthetized with urethane. Bethanechol (BeCh)-stimulated acid secretion was definitely inhibited by bicuculline, a GABA antagonist, and strychnine, a glycine antagonist, but not by picrotoxin and pentylenetetrazol, GABA antagonists. The inhibitory effect of bicuculline and strychnine was accompanied by vigorous convulsions. Only the bicuculline-induced inhibition was still seen in d-tubocurarine paralyzed rats, and it was abolished in spinal rats. 2-Deoxy-D-glucose (2-DG)-stimulated acid secretion was apparently depressed by all the GABA antagonists of bicuculline, picrotoxin and pentylenetetrazol. The inhibitory effect of picrotoxin, but not bicuculline, on the 2-DG stimulation was still elicited in spinal rats. Inhibition of acid secretion stimulated by pentobarbital, a centrally acting secretagogue, was produced by picrotoxin and pentylenetetrazol in spinal rats. These findings suggest that bicuculline acts centrally to inhibit acid secretion stimulated both peripherally by BeCh and centrally by 2-DG, besides nonspecific mechanisms due to convulsions, and the action would be directed to centers which are implicated in stimulation of the sympatho-adrenomedullary system; picrotoxin and pentylenetetrazol also act centrally to inhibit 2-DG- or pentobarbital-stimulated acid secretion through depression of the central vagal tone which leads to inhibition of gastric acid secretion.     

Central GABA receptor stimulants as potential novel antihypertensive agents

γ-Aminobutyric acid (GABA) undoubtedly plays an important role as an inhibitory transmitter in the central nervous system. In recent years, evidence has accumulated which strongly suggests that GABA may specifically play a role in the central regulation of cardiovascular homeostasis. GABA apparently mediates a tonic hindbrain inhibition of vagal bradycardia, probably at nucleus ambiguus. In addition, evidence also suggests an additional GABA inhibitory input in the forebrain to sympathetic structures, possibly in the area of the periventricular hypothalamus. Thus, there appear to be at least two anatomically distinct and physiologically opposed GABAergic inhibitory mechanisms which function to control resting heart rate and reflex vagal activity. GABA also seems to be involved to some degree in the control of vasopressin release and respiratory function. Because of the physiological and pharmacological effects of centrally administered GABA or GABA mimetics, it is suggested that such agents might provide the basis for a new class of antihypertensive agents. Activation of central GABA receptors consistently reduces blood pressure and heart rate by a reduction in centrally mediated sympathetic nervous activity and, perhaps, a reduction in vasopressin release. Thus far, the GABA mimetics, THIP, imidazole-4-actic acid, muscimol, isoguvacine, isoarecaidine, kojic amine, as well as GABA itself, have all been shown to reduce blood pressure when centrally administered. Conversely, GABA antagonists, such as bicuculline and picrotoxin, raise blood pressure. Prodrugs of GABA or of other GABA mimetics can be used to allow for systemic administration of these agents with subsequent central penetration to provide an antihypertensive effect. Finally, it is suggested that the interaction of GABA with benzodiazepine receptors may allow for the development of new agents which, in addition to reducing stress-induced cardiovascular responses, may prevent the development of hypertension.     

Clonidine inhibition of pancreatic secretion in rats: a possible central site of action

The effects of clonidine on pancreatic secretion were studied in rats fitted with chronic or acute fistulas. Subcutaneous and intracerebroventricular injections of clonidine in conscious rats induced a dose-dependent inhibition of basal pancreatic secretion involving volume, bicarbonate output and protein output with an ED50 of about 10 micrograms/kg. Clonidine inhibition of pancreatic secretion was not dependent on the associated inhibition of gastric acid output. In conscious rats, the pancreatic inhibitory effect of clonidine was completely antagonized by yohimbine and slightly by piperoxane and prazosin. Propranolol, mianserin, naloxone and cimetidine did not antagonize the clonidine effect. Clonidine decreased the basal pancreatic secretion in anaesthetized rats and this action was completely reversed by yohimbine. Clonidine inhibited the pancreatic secretion stimulated by 2-deoxyglucose. This effect was reversed by yohimbine, while prazosin had no effect. Clonidine did not inhibit the pancreatic secretion induced by electrical stimulation of the vagus nerves. These results suggest that clonidine inhibition of pancreatic secretion is mediated through alpha 2-adrenergic receptors, and at least in part by a central nervous system mechanism. Yohimbine alone increased basal pancreatic secretion in conscious rats. This suggests that alpha 2-adrenergic receptors might be involved in the physiological nerve tone to the pancreas.     

Inhibition of gastric acid secretion by intracerebroventricularly administered prostaglandin e2 in anaesthetized rats

1 The effect of intracerebroventricularly (i.c.v) administered prostaglandin E2 (PGE2) on gastric acid secretion was studied in anaesthetized rats. 2 Intracerebroventricular injections of 1 and 3 micrograms of PGE2 inhibited gastric acid secretion induced by insulin, electrical vagal stimulation and acetylcholine in a dose-dependent manner. 3 Intravenous injections of 1,3 and 10 micrograms of PGE2 had no effect on insulin-stimulated gastric acid output. 4 The results indicate that upon i.c.v. administration PGE2 inhibits gastric acid secretion by acting centrally and not peripherally after leakage from the central nervous system.     

Possible roles of prostaglandins in the hypothalamus (author's transl)]

The last decade has been the most prolific and stimulating period in the area of prostaglandin (PG) study. Since PGs were found in the hypothalamus and cerebrospinal fluid, and were released from the central nervous system (CNS) spontaneously and in response to chemical or electric stimulation, many investigators have been engaged in studying their effects in the CNS. In fact, PGs have a wide range of pharmacological actions in the CNS. Relatively large doses of PGs have to be given centrally to produce some effects. On the other hand, some types of PGs, when applied centrally in doses of a few ng, stimulate the hypothalamus or the pituitary gland to increase secretion of hypothalamic and anterior and also posterior pituitary hormones. Physiological investigations of PGs have been aided by the use of inhibitors of their synthesis; aspirin, indomethacin etc. These compounds inhibit secretion of the hormones from the hypothalamus as well as the pituitary, suggesting that endogenous PGs exert a functional role for the hormone secretion. To produce fever, PGEs have to act on the preoptic anterior hypothalamus, and aspirin and indomethacin decrease fever produced by pyrogens but not PGEs. Pyrogens produce fever by increasing synthesis and release of PGEs. Hypothalamic PGEs play a role as a central transmitter or modulator in temperature regulation.     

Neuropeptides and gastric mucosal homeostasis

The role of central nervous system (CNS) in regulation of gastric function has long been known. The dorsal vagal complex (DVC) has an important role in regulation of gastric mucosal integrity; it is involved both in mucosal protection and in ulcer formation. Neuropeptides have been identified in DVC, the origin of these peptides are both intrinsic and extrinsic. Neuropeptides are localized also in the periphery, in afferent neurons. The afferent neurons also have efferent-like function in the gastroinetestinal tract, and neuropeptides released from the peripheral nerve endings of primary afferent neurons can induce gastric mucosal protection. Centrally and /or peripherally injected neuropeptides, such as amylin, adrenomedullin, bombesin, cholecystokinin, neurotensin, opioid peptides, thyreotropin releasing hormone and vasoactive intestinal peptide, influence both the acid secretion and the gastric mucosal lesions induced by different ulcerogens. The centrally induced gastroprotective effect of neuropeptides may be partly due to a vagal dependent increase of gastric mucosal resistance to injury; activation of vagal cholinergic pathway is resulted in stimulation of the release of mucosal prostaglandin and nitric oxide. Furthermore, release of sensory neuropeptides (calcitonin gene-related peptide, tachykinins) from capsaicin sensitive afferent fibers are also involved in the centrally induced gastroprotective effect of neuropeptides.     

Central actions of AD-1211, an annalgesic lacking common opiate features

The site of the analgesic action of AD-1211, the less active stereoisomer, and its pharmacological features were investigated. AD-1211, as well as as pentazocine and morphine, blocked the reflex hypertension caused by injection of both bradykinin and bradykinin plus PGE₁ into the splenic artery of dogs. In the rat or mouse writhing test, the analgesic activity of AD-1211 after intraperitoneal and intracisternal administration was equal to and more than 40 times, respectively, that after intravenous administration. The analgesic activity of AD-1211, unlike that of pentazocine and morphine, was incompletely reversed by naloxone and was not attenuated even by its repeated administration for 7 days in the mouse writhing and tail pressure test, respectively. AD-1211, unlike pentazocine and/or morphine, lacked some effects on central nervous, respiratory and cardiovascular function in conscious animals. These results demonstrate that AD-1211 produces its analgesic action through a central mechanism but lack some of the common pharmacological actions shown by morphine-like analgesics.     

Regulation of gastrin release in the dog by α2-adrenoceptors

1 The purpose of the present study was to analyse the effects of the α₂-adrenoceptor agonist medetomidine and the antagonist yohimbine on gastrin release in conscious dogs. 2 Gastrin secretion was investigated under both basal conditions and stimulation by 2-deoxy-D-glucose, food or bombesin. 3 Basal gastrin under fasting conditions was significantly reduced by medetomidine and increased by yohimbine. 4 2-deoxy-D-glucose-induced gastrin increase was fully inhibited by medetomidine; this effect was antagonized by yohimbine. 5 Medetomidine significantly inhibited food-induced increase in plasma gastrin; under these conditions yohimbine was without effect per se, but significantly antagonized the inhibitory action of medetomidine. 6 Gastrin release induced by bombesin was not affected by medetomidine or yohimbine. 7 These results suggest that α₂-adrenoceptors play an inhibitory role under conditions in which gastrin release is mainly mediated through cholinergic and non-cholinergic nervous pathways; in contrast, they do not indicate the presence of α₂-adrenoceptors on G cells of the dog stomach.