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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.

Buflomedil is a vasoactive drug used in the treatment of peripheral vascular disease, and seems to be an antagonist of both alpha 1- and alpha 2-vascular adrenoceptors. CRL40634 and CRL40598 are metabolites of buflomedil and also possess vasoactive properties. The purpose of this study was to investigate whether buflomedil, CRL40634 and CRL40598 have antagonist activity on the alpha 2-adrenoceptors involved in the inhibition of exocrine pancreatic secretion. In acute pancreatic fistula rats, buflomedil, CRL40634 and CRL40598 did not suppress the inhibitory effect of clonidine against 2-deoxy-glucose-induced pancreatic secretion. However, all three drugs inhibited 2-deoxy-glucose-induced pancreatic secretion, their order of potency being CRL40598 greater than CRL40634 greater than buflomedil.

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Alcohol intake is a major problem in drug addicts, and it is not clear whether the effects of alcohol and opiates are additive or potentiating. Vagally stimulated pancreatic secretion in rats is potently inhibited by opiates acting centrally at mu-receptors. In the present experiments, we determined the effects of methadone on 2-deoxyglucose (2DG)-stimulated pancreatic secretion in rats treated with acute (1.9 g/kg.3 h, intravenously) or chronic (1 or 3 month drinking) ethanol. In both acute and 1 month chronic alcoholic rats, methadone administered at its 50% inhibitory dose (ID50) reduced by about 50% 2DG-stimulated pancreatic secretion of sodium, bicarbonate and protein, and ethanol had only faint, nonsignificant inhibitory effects. In 3 month chronic alcoholic rats, similar results were obtained, but methadone inhibited 2DG-stimulated pancreatic secretion by 60 to 90% in these older rats. No significant interaction was found in any condition between ethanol and methadone, suggesting that they had only additive, but not potentiating effects in this method.

The recently described compound CRL41405 displays central effects suggesting possible antidepressive and awakening properties. In order to further analyze the pharmacology of this compound, its effects were studied on basal and stimulated pancreatic secretion in anaesthetized rats. CRL41405 alone (7-20 mg/kg, sc) had no effect on basal pancreatic secretion. Larger doses (67-200 mg/kg) increased basal secretion through the stimulation of cholinergic muscarinic receptors, the effect being antagonized by atropine. CRL41405 (20 mg/kg) suppressed the 2-deoxyglucose-induced (but not the acetylcholine-induced) stimulation of pancreatic secretion through an alpha-2 adrenoceptor inhibitory mechanism that was blocked by idazoxan (0.3 mg/kg, sc). In addition, a beta adrenoceptor mediated stimulation of sodium and bicarbonate excretion (blocked by propranolol) was evidenced when the alpha-2 inhibition was suppressed by idazoxan. Under alpha-2 adrenoceptor blockade, water and electrolyte stimulation by CRL41405 could be demonstrated on basal, 2-deoxyglucose-induced and acetylcholine-induced pancreatic secretion. This original profile makes CRL41405 a unique drug in pancreatic pharmacology.

Male Wistar rats, fed a standard normal laboratory diet, drank ad libitum a 20% ethanol solution for 3 months. Basal and 2-deoxy- D -glucose (2DG) stimulated pancre

The effects of intracerebroventricular injections of synthetic ovine β-endorphin were tested in conscious rats with gastric and pancreatic fistulas. In the range of 0.8 to 25 μg injected in the third ventricle of the brain, basal gastric and pancreatic secretions were strongly inhibited in a dose-dependent manner. Pancreatic volume, bicarbonate output, and total protein output were similarly inhibited, while the bicarbonate concentration was only slightly changed. Similar effects were noted after the administration of morphine. In the present model system, morphine was 20–30 times less active than β-endorphin on a molar basis. β-Endorphin inhibition of pancreatic secretion was reversed by naloxone, suggesting that opiate receptors are involved in this phenomenon. Gastric acid secretion participated in the pancreatic effects of β-endorphin to only a slight extent, since pancreatic inhibition by the endorphin was decreased only slightly in rats with gastric fistula in which gastric juice was diverted and did not reach the duodenum. The comparison of intravenous and intraventricular injections of β-endorphin and morphine suggested that the observed inhibitions originated in the central nervous system. No effects were detected after the administration of α-endorphin, Met-enkephalin or Leu-enkephalin, although pancreatic secretion was measurably inhibited by longacting synthetic enkephalin analogues.

Summary— The effects of modafinil and adrafinil, 2 drugs that induce locomotor hyperactivity, and those of the parent compounds CRL 40467 and CRL 40385, were studied on the external pancreatic secretion of anaesthetized and conscious rats. In anaesthetized rats modafinil, adrafinil, and CRL 40385 antagonized the central vagal stimulation of protein output induced by 2-deoxy-D-glucose in the pancreatic juice. In conscious rats, modafinil and adrafinil inhibited the output of protein in the basal interdigestive pancreatic secretion. Modafinil was more active than adrafinil as an inhibitor of pancreatic secretion. The effects of modafinil and adrafinil were different from those of sympathetic amines and dopamine: they did not stimulate the output of bicarbonate in anaesthetized rats, and pancreatic inhibition observed in conscious rats was not inhibited by either yohimbine or prazosin.

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 ID 50 of about 1 mg/kg and an ID 100 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.

Biliary secretion was studied in normolipedemic rats after a 7 day treatment with the hypolipidemic drugs, tiadenol (bis-(hydroxyethylthio)-1,10-decane), clofibrate and clofibride (chloro-4-phenoxy-2-methyl-2-propionate of dimethylcarbamoyl-3-propyl). All three drugs decreased blood cholesterol and total lipids, increased liver weight and liver catalase content, and decreased biliary excretion of cholesterol. The biliary concentrations of bile salts, phoslipids and cholesterol decreased to a variable extent, in such a way that ratio of bile salts + phospholipids to chloresterol was increased by the drugs. The bile salt independent fraction was increased. The effects were qualitatively similar for all three drugs tested, but quantitative differences appeared for some of the parameters.

The effects of somatostatin on the secretions of the exocrine pancreas were studied in anesthetized and conscious fistula rats. Somatostatin resulted in a dose-dependent decrease of basal secretion (flow, bicarbonate, protein) in conscious rats. In anesthetized rats, basal secretion was initially augmented by bolus injections of 10 to 50 microgram per kg and was subsequently decreased by venous infusions of somatostatin at 1.5 to 100 microgram.kg-1.hr-1. This inhibition, which was poorly dose dependent, was greater for protein secretion than for that of water and electrolytes. Somatostatin inhibited caerulein-stimulated protein secretion by 40 to 50% but had no effect on secretion stimulated by exogenous and endogenous secretin. Somatostatin markedly inhibited secretion stimulated by 2-deoxyglucose and by electrical stimulation of the vagus nerves in a dose-dependent fashion (protein and bicarbonate exhibited a maximal inhibition of 85%). Acetylcholine-stimulated secretion was also inhibited by somatostatin, but the maximal inhibitions observed were only 505 for protein and 60% for bicarbonate. These findings agree with the hypothesis that somatostatin infusion leads to both a decrease of acetylcholine release at nerve endings and to a direct inhibition at the level of pancreatic effector cells.

A diet containing citrates increased bile salts and phospholipids concentration in the rats' bile, while a diet containing a hypolipemic factor (tiadenol) decreased cholesterol. No potentiation was obtained when the diet contained both factors.

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.

Pancreatic secretion in anesthetized rats with acute fistulas was provoked by caerulein, acetylcholine, electrical stimulation of the vagus nerves or by 2-deoxy-D-glucose (2-DG). Venous infusions of norepinephrine, isoprenaline or dopamine inhibited the 2-DG-stimulated enzyme secretion but not that provoked by caerulein, acetylcholine or vagal electrical stimulation. Intracerebroventricular administration of norepinephrine or isoprenaline also inhibited 2-DG-stimulated enzyme secretion. It was confirmed that the amines stimulated water and electrolyte secretion by the pancreas in the order of potency isoprenaline greater than norepinephrine greater than dopamine. The results are consistent with a model whereby norepinephrine and isoprenaline exert their effect on pancreatic secretion via a central inhibition of vagal drive to the pancreas, together with a direct stimulating effect on water and electrolyte secretion at the level of pancreatic cells.

The effects of the drug CRL 40827 and salbutamol, a structurally related compound, on exocrine pancreatic secretion in acutely fistulized anaesthetized rats and in chronically fistulized conscious rats were studied. CRL 40827 and salbutamol (0.05-0.45 mumol/kg per min, for 2 h) increased the basal secretion of fluid and bicarbonate in anaesthetized rats. The effect of CRL 40827 (15% of the maximal effect of secretin) was suppressed by propranolol (a non-specific beta-adrenoceptor antagonist), by ICI 118551 (a beta 2-antagonist) and by atenolol (a beta 1-antagonist). The effect of salbutamol (25% of the maximal effect of secretin) was suppressed by propranolol and ICI 118551 but was only slightly decreased by atenolol. The stimulant peak effects of CRL 40827 and salbutamol on volume and bicarbonate output were additive to those of 2-deoxy-glucose whereas the effect of 2-deoxy-glucose on protein output was not changed by either drug. CRL 40827 and salbutamol decreased the basal interdigestive protein output in a dose-related manner in conscious rats. CRL 40827 was 27 times less potent than salbutamol. The pancreatic outputs of fluid, bicarbonate and protein after an intragastric meal were decreased by both drugs. However, only salbutamol significantly decreased the cumulative effect of the meal on protein output compared to basal output. These results suggest that the stimulant effect of salbutamol on the pancreatic secretion of fluid and bicarbonate depends mainly on beta 2-adrenoceptors whereas that of CRL 40827 involves adrenoceptors of an as yet undefined subtype.

The effects on bile secretion of classical stimulants and depressants of the parasympathic system were reinvestigated in the anaesthetized rat. Antimuscarinic drugs and vagotomy did not decrease bile