C Vaille's research while affiliated with Unité Inserm U1077 and other places

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.

Pancreatic secretion is controlled by neural and endocrine mechanisms. The administration of 2-desoxyglucose (2DG) to rats stimulates pancreatic secretion through a mainly vagal pathway, and provides an useful pharmacological model to study the agents (especially opiates and adrenergic drugs) which can modulate this neural pathway. In the present study, basal and 2DG-stimulated pancreatic secretion were measured in anesthetized rats. Nalbuphine had no effect on basal secretion; it antagonized 2DG-induced pancreatic stimulation in a dose-related fashion between 0.5 and 15 mg/kg iv. The effect of nalbuphine was suppressed by naloxone, but not by alpha and beta-adrenoceptor blocking agents, indicating an essentially opiate effect. In order to test whether an inhibition of kappa receptors participates in the nalbuphine effect, centrally or peripherally acting kappa agonists were associated with nalbuphine. Neither U50488H, nor ICI204448 changed 2DG stimulation and nalbuphine effect. In conclusion, the effect of nalbuphine on 2DG-stimulated pancreatic secretion was similar to that of methadone and buprenorphine, required larger doses, and seemed to mainly involve mu receptors.

Pancreatic secretion is controlled by neural and endocrine mechanisms. The administration of 2-desoxyglucose (2DG) to rats stimulates pancreatic secretion through a mainly vagal pathway, and provides an useful pharmacological model to study the agents (especially opiates and adrenergic drugs) which can modulate this neural pathway. In the present study, basal and 2DG-stimulated pancreatic secretion were measured in anesthetized rats. Nalbuphine had no effect on basal secretion; it antagonized 2DG-induced pancreatic stimulation in a dose-related fashion between 0.5 and 15 mg/kg iv. The effect of nalbuphine was suppressed by naloxone, but not by alpha and beta-adrenoceptor blocking agents, indicating an essentially opiate effect. In order to test whether an inhibition of kappa receptors participates in the nalbuphine effect, centrally or peripherally acting kappa agonists were associated with nalbuphine. Neither U50488H, nor ICI204448 changed 2DG stimulation and nalbuphine effect. In conclusion, the effect of nalbuphine on 2DG-stimulated pancreatic secretion was similar to that of methadone and buprenorphine, required larger doses, and seemed to mainly involve mu receptors.

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.

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.

2-deoxyglucose stimulates pancreatic secretion through a mainly vagal neural pathway. Buprenorphine antagonized this stimulation in a dose-related fashion between 0.017 and 0.45 mg/kg. i.v. The effect of buprenorphine was suppressed by naloxone, but not by alpha and beta-adrenoceptor blocking agents. The effect of methadone was similar, at doses about ten times larger.

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.

Modannil ~~ a 1:. ecently .develqped dru.g with a new phannacologtcci1 profile. If induces hXJilerlocolnotot activity tn tntce: and J)'rovokes. wake-up. :reactions rn: several alilirtal species. an~ iJl man. "rhi' s .effect a;~pe, ars dtffe.rent ;from tjlat of ampheta:mfne, an:d seems related to , the sttrnulalion ef .some. classes of centx;al alpha:-adrenocepl ors. We repotte~t preVlously that modafti;HI iU,h:-ibits the central ~eural sUmula:tton of pancreatic secretion :induced by 2-deoxy-D-glucose (2Dq). The pux:ppse of the present sttidy was .to artal~e tnis effect in tenus of aclri;meFgfc and pptate ·:r;ecptots, b~ using ap.t~gpntsts and compa;Fing the eff~~ts of mo.clafinil with thos. e of the mu. opiate methadone. Hrethcme anestnetlzed. rl;l.ts with, a pancreatic· fist. ula. re~etxed an iY iinjecHorr ·of 75 mg/~ 2DG, a dose Jnducing a submrumnal pancreatic sttrnuiation. Modafihil (28 to 750 mg/kg,, ip) produced a dose~rel'ated in:hibtHon oi 2DG-sttmulated· ·tota:l ·protelp, biear'Qonate and voluJile .ofjuice, with an ED50 of about 50 mg/~. · and reaching 85%. after ,250 mg/kg. The effect of 250 mg{kg, .of modafinil was completely Jl:t;"evente.d by tdazoxan .(0.3 mg/;kg., se). or 'by the ·as~ocfe~.U:on of idazexan + pra,zosln + proprandlol, but neither by· prazostil. . alone (0.'5 mgf,.kg, se) nor by naloxone (1 mg/:kg, se). , Metlladome (5 ~g/~ •. ~) <Uso suppre~ed the 2PG stunalation Q'ut, in contrast 'to mo€l'afinil, the effect of methadone was not prevented by tbe association of 'idazox:ap + p,~:azost!l + Im~pranoloJ, and ·was completely snQp~e_ ssed by nalo:xone H mg/kg,scl. In concluston, llie ' irlhtbition ot 2. DG-sttmu1ated pancteaUc secretion by moda:finll ~s related to the activation of aJpha 2-aqrenoceptors probably, located in the central nexvous system, whereas no :emdence was fou:nd of any interaction ·Of' this drug wttll apiate recepJors,,

2-deoxyglucose stimulates pancreatic secretion through a mainly vagal neural pathway. Buprenorphine antagonized this stimulation in a dose-related fashion between 0.017 and 0.45 mg/kg. i.v. The effect of buprenorphine was suppressed by naloxone, but not by alpha and beta-adrenoceptor blocking agents. The effect of methadone was similar, at doses about ten times larger.