Counteracting effect of papaverine on morphine inhibition of gastrointestinal transit in mice.

Oral papaverine has been shown to be capable of antagonizing the constipation induced by a single dose of oral morphine. The primary aim of the present study was to ascertain whether papaverine is also capable of counteracting morphine-induced decrease of upper gastrointestinal transit (UGT) after repeated parenteral administration of the opioid. We next investigated the mechanisms(s) responsible for the counteracting effect of papaverine, by analysing whether this effect was changed by pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME), dexamethasone, indomethacin or capsaicin. Papaverine, co-administered with morphine, counteracted the morphine-induced decrease in UGT in mice pretreated with morphine for 3 days but did not do so in naive animals. The counteracting effect of papaverine was antagonized by L-NAME, but not by indomethacin. In mice pretreated with both morphine and dexamethasone, papaverine failed to antagonize the effect of morphine. Capsaicin pretreatment completely abolished the effect of a single dose of morphine, the effect being partially restored by the 3 days pretreatment with morphine. In mice pretreated with both capsaicin and morphine, the UGT decrease elicited by morphine was lower than in the other experimental groups and was not modified by papaverine. Our results show that papaverine can counteract the morphine inhibition of UGT in mice repeatedly exposed to the opioid. Papaverine exerts its action through a nitric oxide synthase-mediated mechanism; this mechanism is only effective after repeated morphine administration and does not operate when capsaicin-sensitive afferent neurones are ablated.

Interaction of beta-carbolines with central dopaminergic transmission in mice: structure-activity relationships.

Although several beta-carboline alkaloids display hallucinogenic properties in humans, their mechanism of action remains unclear. To ascertain their influence on central dopaminergic transmission, in this study we investigated the facilitating effect of low doses of various beta-carbolines on L-DOPA (250 mg/kg)-induced stereotypy in mice. Harmaline (0.075, 0.15 and 0.35 mg/kg) and harmine (0.15, 0.35 and 0.75 mg/kg) powerfully enhanced the degree of stereotypy, whereas 6-methoxy-harmalan, 6-methoxy-harman and harman were far less potent, augmenting stereotypy only at much higher doses (3 mg/kg). 6-Methoxy-tetrahydro-beta-carbolin (6-MeO-THBC) had only a weak effect at the dose of 3 mg/kg and tetrahydro-beta-carbolin (THBC) had no effect up to the dose of 3 mg/kg. The Ca(2+)-channel blocker nimodipine (2.5 mg/kg) only slightly antagonized harmaline (0.15 mg/kg) facilitation of L-DOPA-induced stereotypy.

Ocular absorption and distribution of bendazac after topical administration to rabbits with different vehicles.

Ocular and systemic absorption of bendazac was investigated after topical administration to rabbits of 0.5% solutions of bendazac lysine in different polysaccharide vehicles. The results show that the drug is absorbed into the retina-choroid via an extracorneal, or sclero-conjunctival route; the iris and the ciliary body are presumably supplied via both the transcorneal and the extracorneal pathways. The extent of absorption via the extracorneal route is not related to vehicle viscosity but rather to the chemical features of vehicle. The transcorneal penetration appears to be hindered by the binding of the drug to corneal tissues.

The alpha 1-blocker dapiprazole inhibits diuresis but not drinking and feeding induced by U-50,488H.

To further explore the interaction between opiates and catecholamines in the control of water balance, we studied the effects of the alpha 1-adrenoceptor antagonist dapiprazole on the modifications in drinking and diuresis produced by U-50,488H (a selective kappa-opiate agonist), morphine, naloxone, and amphetamine in rats. Because animals were maintained in a free-feeding paradigm and water intake is also controlled by feeding (prandial drinking), food intake was also measured. At doses administered (3-6 mg/kg, IP), dapiprazole had no effect on basal food and water intake or on diuresis. Nor did it modify changes in feeding and drinking produced by U-50,488H, morphine, naloxone, and amphetamine. It did, however, antagonize the diuretic effect of both U-50,488H and amphetamine. In addition, suppression of diuresis was obtained by combining doses of dapiprazole and morphine or naloxone that were devoid of antidiuretic effects when administered independently. A further experiment showed that diuresis produced by water load was also prevented by dapiprazole. alpha 1-Adrenoceptors thus appear to play a role in the regulation of water balance in a condition of free access to water, inhibiting diuresis without affecting drinking.

Effects of trazodone and m-chlorophenylpiperazine (m-CPP) on acute dependence in mice.

The antidepressant trazodone and its main metabolite, m-CPP, having an antiserotoninergic and serotoninergic activity respectively, were studied in an acute dependence model in mice, to establish whether 5-hydroxytryptaminergic systems are involved in the manifestations of acute opiate dependence and in its development. When drugs were administered 15 min before naloxone, all signs of abstinence decreased, with the exception of teeth chattering that was increased by m-CPP and unaffected by trazodone. When injected 15 min before morphine, jump episodes were decreased by the highest doses of both drugs, while teeth chattering was decreased by m-CPP only. When administered 1 h before morphine, trazodone increased paw and head shakes and mCPP decreased teeth chattering and both left the other signs unaffected. Serotoninergic systems seem to have a significant role in events involved in the withdrawal syndrome and a minor one in those leading to the development of dependence.

Antinociceptive effects of trazodone and m-chlorophenylpiperazine (mCPP) in mice: interaction with morphine.

1. The antidepressant trazodone and its main metabolite m-chlorophenylpiperazine (mCPP) were investigated for their analgesic properties and their sensitivity to a threshold dose of morphine in acetic acid abdominal constriction and hot plate tests. 2. The drugs elicited hypoalgesic effects at about the same doses in the two analgesic assays. 3. Naloxone (2 mg/kg i.p.) prevented the hypoalgesia of trazodone but not of mCPP in the hot plate test. The opiate antagonist did not affect the responses of both drugs to the writhing test. 4. Subanalgesic doses of the two drugs increased the sensitivity to morphine in both assays. The results further support the suggested role played by opioid and 5-HT systems on depression.

Ocular disposition of acetaminophen and its metabolites following intravenous administration in rabbits.

Time-courses of both 'total' (unchanged plus metabolized) and unmetabolized acetaminophen were investigated in plasma and ocular tissues of rabbit after intravenous administration. The drug freely diffuses across the haemato-ocular barriers, reaching eye levels equal to those in the plasma; ocular concentrations are higher than those of all other investigated drugs. The time-course in aqueous is superimposable to that observed in the plasma; in other ocular tissues it is much slower. There is evidence of an ocular metabolism or a concentration into the eye of minor metabolites formed elsewhere.

Some pharmacological characteristics of the guinea pig ileum opioid system activated by cholecystokinin.

Naloxone, added after contractions induced by CCK-8 on the guinea pig ileum preparation, elicited a contraction attributed to the release of endogenous opioid which could inhibit the excitatory action of the peptide. With large concentrations of CCK-8, the preparation gave reproducible responses with time. Naloxone, added before the peptide, protracted the excitatory response to CCK-8, but not its height. Morphine decreased the response to CCK-8 but simultaneously raised the response to naloxone. The latter effect appeared very similar to the withdrawal contraction observed after brief exposure of the opioid in the guinea pig ileum to opioids. Clonidine, and alpha-2 adrenoceptor agonist, and nifedipine, a calcium channel antagonist, both known to interfere with tolerance and physical dependence, affected the excitatory response to CCK-8 and the subsequent response to naloxone in a different way.

Effects of dapiprazole, clonidine and yohimbine on the development of dependence and withdrawal behaviour in mice.

There is evidence that central noradrenergic hyperactivity is involved in the manifestation of the major signs and symptoms of the opiate withdrawal syndrome. In order to assess whether or not the noradrenergic system is also implicated in the development of opiate dependence, we studied dapiprazole, an alpha-1 selective adrenoceptor antagonist, clonidine and yohimbine using the acute dependence model in mice. When administered just before naloxone, after dependence development, all three drugs reduce abstinence signs. When injected 15 min before morphine to observe the drugs' effects on the development of dependence, dapiprazole depresses all the symptoms registered while clonidine decreases only jumping, but increases paw and head shakes. None of these drugs affects the naloxone precipitated withdrawal syndrome when injected 1 h before morphine. It is suggested that the noradrenergic system is involved in both the manifestation of the withdrawal syndrome and in the development of opiate dependence. Diapiprazole may be a useful tool in patients and in pharmacological studies of dependence and abstinence.

Endocrine pancreatic function in insulin-dependent diabetic pregnant women.

In order to better understand the role of A- and B-cell function in diabetic pregnancy, we studied four groups of pregnant women at week 34-36 of gestation. Seventeen were healthy controls (C), 24 had gestational diabetes (GD), 16 had type 2 diabetes (NIDD) and 37 had type 1 diabetes (IDD). At times -20, 0, 20, 30, 45, 60, 90 and 120 min from the beginning of a 30 min infusion of 30 g of arginine intravenously, plasma glucose, glucagon (IRG) and C-peptide (CPR) were measured. Plasma glucose was higher in diabetic than in control subjects. IRG values were also higher in the GD and the NIDD women. CPR values were similar to, or slightly higher than control values in the GD and the NIDD and were much lower in the IDD women. All three variables increased during the arginine infusion in all groups, with the exception that CPR remained unchanged in the IDD. The CPR/IRG molar ratio was similar in control, GD and NIDD women; in the IDD, it was much smaller than in the other groups and was not affected by arginine. In all the diabetic patients, IRG was negatively correlated with the maternal weight gain and in the IDD IRG was positively correlated with the increase in the insulin need and with the CPR levels. In conclusion diabetes appeared to enhance the A-cell function also in pregnancy, possibly impairing the 'facilitated anabolism' and stressing the 'accelerated starvation' which are typical of normal pregnancy. Glucagon was confirmed as one possible determinant of the insulin resistance seen in diabetic pregnancy.

Gastro-entero-pancreatic hormones in amniotic fluid from normal and diabetic pregnant women.

Clinical applications of analyses of hormones in amniotic fluid (AF) have recently been increased. In diabetic pregnancy, determinations of insulin and C-peptide in AF have been suggested as good indicators of the status of the foetus. We have investigated the pancreatic alpha and beta cell function by measuring insulin (IRI), C-peptide (CPR), glucagon (IRG), somatostatin (SLI), and gastric inhibitory polypeptide (GIP) in amniotic fluid collected during basal conditions or 2 h after an arginine test in 92 diabetic and 32 non-diabetic pregnant women. During basal conditions, in diabetic pregnant women, IRI, CPR and the insulin: glucagon molar ratio (I/G) were all significantly higher while amniotic fluid-IRG was significantly lower than in the controls. After arginine stimulation, IRI increased in AF of the diabetic pregnant women but not in AF of the controls while no differences were observed in AF-GIP and AF-SLI concentrations. Higher IRI and CPR, as well as lower IRG values were significantly related to poor maternal metabolic control. The occurrence of neonatal morbidity including macrosomia was significantly associated with increased AF, IRI and CPR concentrations after an arginine challenge and these factors were the most sensitive predictors of neonatal morbidity in infants of diabetic mothers. Increased AF glucose concentrations and I/G ratios were related to neonatal hypoglycaemia; jaundice and respiratory distress syndrome were associated to low concentrations of SF-IRG.

Amniotic fluid insulin, C peptide concentrations, and fetal morbidity in infants of diabetic mothers.

Glucose, insulin, C peptide, and insulin antibody concentrations were measured in amniotic fluid collected under basal conditions and 2 hours after an arginine challenge from 61 insulin-treated diabetic women (12 basal and 49 after arginine challenge) and 31 nondiabetic pregnant women in late gestation (23 basal and eight after arginine challenge). The insulin, C peptide, and glucose concentrations were significantly higher in diabetic pregnant women than in nondiabetic pregnant women in each case. In the amniotic fluid obtained after arginine challenge in diabetic pregnant women, C peptide concentration was correlated with both insulin concentration (r = 0.61) and birth weight (r = 0.53). The insulin and C peptide concentrations were significantly higher (p less than 0.025) in samples from diabetic pregnancies associated with fetal morbidity than from diabetic pregnancies without fetal morbidity. Basal amniotic fluid insulin and C peptide concentrations were slightly greater in overweight infants of diabetic mothers compared to those of normal weight, whereas the differences for insulin and C peptide concentrations in the amniotic fluid obtained after arginine challenge were highly significant (p less than 0.0125 and p less than 0.0005, respectively). Finally insulin and C peptide concentrations in the amniotic fluid obtained after arginine challenge in diabetic pregnant women showed a correlation with maternal metabolic control but not with the degree (White classification) of maternal diabetes. No or negligible interference of insulin antibody in the radioimmunoassay of insulin in amniotic fluid was observed.