C. Vaille

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.

Modulation of Stimulated Pancreatic Secretion by Sympathomimetic Amines in the Rat

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.

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 anesthetized 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.

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.

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.

Effect of modafinil on pancreatic exocrine secretion in rats. A comparison with adrafinil and related drugs.

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.

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)

Modulation by alcohol and methadone of 2‐deoxyglucose‐stimulated pancreatic secretion in the rat

Summary— 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 μ‐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/kgṁ3 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 model.

Effects of CRL 40827 and salbutamol on exocrine pancreatic secretion in rats

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.

Independence from Vagal Control of Biliary Secretion in the Rat

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