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PubMed1986

Neonatal capsaicin modifies morphine withdrawal signs in the rat.

Rats received injections of either capsaicin (50 mg/kg, s.c.) or the capsaicin vehicle at two days of age. When the animals were 90-120 days of age they were implanted with morphine or placebo pellets (s.c.) for 3 (one pellet) or 6 (3 pellets) days. Naloxone (0.4 mg/kg, s.c.) produced no effects in the placebo-pelleted groups but elicited salivation, lacrimation and rhinorrhea in the morphine-treated animals. These abstinence signs were less severe in the morphine-pelleted rats (3- and 6-day groups) that were treated as neonates with capsaicin. However, the neonatal capsaicin treatment increased the number of naloxone-precipitated wet-dog shakes in morphine-dependent rats. The increase was statistically significant in rats treated with morphine for 3 but not 6 days. Since capsaicin induces a long-lasting depletion of substance P and other peptides in peripheral and central neurons, it was concluded that substance P or other related peptides may be involved in the expression of some signs of opioid withdrawal.

Animals↗
PubMed1994

Sialogogic activities of SNI-2011 compared with those of pilocarpine and McN-A-343 in rat salivary glands: identification of a potential therapeutic agent for treatment of Sjörgen's syndrome.

1. We examined the sialogogic activities in rat major salivary glands of SNI-2011, in comparison with those of pilocarpine and McN-A-343, and we characterized the subtypes of muscarine receptors that are involved in the sialogogic responses to SNI-2011 and McN-A-343. 2. SNI-2011 at doses ranging from 1 to 10 mg/kg (i.v.) increased the secretion of saliva in a dose-dependent manner. The dose-response curves for SNI-2011 were approximately parallel to curves for pilocarpine but the potency of SNI-2011 was about 25-fold lower than that of pilocarpine. 3. The total volume of saliva secreted in response to McN-A-343 was very much less than that secreted in response to SNI-2011. 4. The salivation induced by SNI-2011 and by McN-A-343 was inhibited by various antagonists with the following rank order of potency: 4-DAMP >> pirenzepine >> AF-DX 116. 5. Our results suggest that the sialogogic effects of SNI-2011 and McN-A-343 are mediated by direct stimulation of M3 receptors in salivary glands and that SNI-2011 may prove useful in the management of xerostomia in patients with Sjögren's syndrome.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1989

Autonomic and subjective responses to alcohol stimuli with appropriate control stimuli.

Previous studies on "craving" for alcohol after exposure to olfactory stimuli for alcohol may be criticized on the grounds that the control stimuli were not really appropriate. We included exposure to a preferred nonalcoholic beverage and to a sweet food item as additional control stimuli in order to better compare the salivary, autonomic, and self-reported craving responses of alcoholics with normal social drinkers. The results indicated that the salivation measure was differentially sensitive to the alcohol stimulus, even when compared to appropriate control stimuli. It is possible that self-reported craving is a biased measure in alcoholic inpatients in treatment.

Adult↗
PubMed1984

In vivo actions of atraxin, a protein neurotoxin from the venom glands of the funnel-web spider (Atrax robustus).

The effects of atraxin, a neurotoxic protein from the venom glands of the funnel-web spider (Atrax robustus), have been studied in anaesthetized monkeys. At doses of 70 and 80 micrograms kg-1 i.v., atraxin caused respiratory disturbances (dyspnoea and apnoea), and profound alterations in heart rate and blood pressure. These doses also caused salivation, lachrymation, skeletal muscle fasciculation and an elevation in body temperature. Concurrent increases in firing were recorded from the phrenic nerve and from respiratory and other skeletal muscles. It is concluded that atraxin produces the same syndrome in primates as that observed with whole milked male funnel-web venom.

Animals↗
PubMed1992

The effects of m-octopamine on salivary flow rates and protein secretion by rat submandibular glands.

1. m-Octopamine given i.v. or i.p. was a potent sialogogue for rat salivary glands. 2. Salivation in response to i.v. m-octopamine was completely abolished by prazosin and phenoxybenzamine. 3. The alpha-type of proteins were secreted in response to all doses of i.v. and i.p. m-octopamine and these were converted into the beta-type with prazosin, but not with yohimbine. 4. m-Octopamine stimulated both alpha- and beta-adrenoceptors and was a much more selective alpha 1-agonist than was the p-isomer.

Adrenergic beta-Antagonists↗
PubMed1996

Synthesis and muscarinic activities of 3-(pyrazolyl)-1,2,5,6-tetrahydropyridine derivatives.

A series of 3-(pyrazolyl)-1,2,5,6-tetrahydropyridine derivatives (B) was synthesized and tested for muscarinic activity in receptor binding assays using [3H]-oxotremorine-M (3H-OXO-M) and [3H]-pirenzepine (3H-PZ) as ligands. Potential muscarinic agonistic or antagonistic properties of the compounds were determined using binding studies measuring their potencies to inhibit the binding of 3H-OXO-M and 3H-PZ. Preferential inhibition of 3H-OXO-M binding was used as an indicator for potential muscarinic agonistic properties; this potential was confirmed in functional studies on isolated organs. All compounds with agonistic properties showed 3H-PZ/3H-OXO-M potency ratios in excess of 20. In contrast, for antagonists this ratio was found to be close to unity. Mono-halogenation resulted in compounds (4b and 4d) with M3 agonistic properties as shown by their atropine sensitive stimulant properties in the guinea pig ileum, but with very little or no M1 activity. Some minor in vivo effects were observed for both these compounds, with the iodinated compound 4d inducing salivation. Compound 4d also showed some positive mnemonic properties in rats where spatial short-term memory had been compromised by temporary cholinergic depletion. These data indicate that some M3 agonism may be desired in therapeutic agents aimed at the treatment of the cognitive deficits of Alzheimer's disease patients.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Synthesis and muscarinic M3 pharmacological activities of 1-azabicyclo[2.2.2]octan-3-one oxime derivatives.

A series of 1-azabicyclo[2.2.2]octan-3-one oximes and related 1-azabicyclo-[2.2.2]-octan-3-one hydroxylamines were synthesized and tested for muscarinic M3 activity. All compounds showed at least some muscarinic binding properties, however, only one member of the series demonstrated mucarinic M3 agonistic properties in vitro (contraction of guinea pig ileum) and in vivo (mydriasis, salivation). In addition, this compound partially reversed the cognitive deficit induced by central cholinergic depletion in two procedures testing memory in the rat, namely the delayed matching to position and swim maze tasks of spatial memory in the rat.

Animals↗
PubMed2004

Nitric oxide and angiotensin II: neuromodulation of thermoregulation during combined heat and hypohydration stress.

We investigated the central role of nitric oxide and AngII on thermoregulation in rats (Rattus norvegicus, Sabra strain,) undergoing heat-stress in euhydration or hypohydration (water deprivation, -10% b.wgt). Experimental rats received AngII (100 pm), 7-nitroindazole-an antagonist of neuronal nitric oxide synthase (7NI-100 nm), or AngII+7NI in a 5-microl bolus intracerebroventricularly (i.c.v.) under light chloroform anesthesia; untreated control rats received saline or DMSO (5%). We used three experimental paradigms: (1) heat defense responses [salivation (STsh), vasodilatation (VTsh) temperature thresholds and heat-endurance] in conscious, heat-stressed (39 degrees C) rats; (2) Western immunoblotting to detect AngII AT(1) and AT(2) receptors and nNOS protein expression; (3) real-time PCR to measure gene transcripts. In the in vivo experiment, 7NI decreased thermoregulatory thresholds, namely, NO had a reciprocal effect that was more pronounced during hypohydration (e.g. euhydration: STsh: -0.7+/-0.01 degrees C, hypohydration: -0.9+/-0.18 degrees C, p<0.05). AngII decreased STsh by 0.9+/-0.18 degrees C (p<0.05) upon euhydration but increased it in hypohydration (+1.7+/-0.28 degrees C, p<0.05). A novel finding was the involvement of AT(2) receptors in thermoregulation, which was more pronounced upon hypohydration. The response to NO was mediated via AT(1) and AT(2) receptors signaling, as well as independently. A synthesis of the results from all experimental paradigms suggests (1) a dominant influence (decrease) of NO on AT(1) receptors, thereby changing AT(1)/AT(2) receptor ratio and their signaling pathway; primarily upon hypohydration; (2) an influence of AngII (increase) on receptor density, more pronounced during hypohydration, at both gene transcription and translation levels; and (3) an effect of AngII on nNOS protein levels, implying a mutual effect of AngII and NO.

Analysis of Variance↗
PubMed2006

Tolerable infusion rate of citrate based on clinical signs and the electrocardiogram in conscious dogs.

BACKGROUND & AIMS: The possible clinical significance of the toxic effects of citrate has not yet been fully clarified. This study was therefore conducted to confirm the toxicity and determine the tolerable infusion rate of citrate administered by rapid intravenous infusion to conscious dogs. METHODS: Citrate solutions were infused via the cephalic vein of 4 conscious dogs at 0.33, 0.67, or 1.33mmol/kg/h up to 1.33mmol/kg. Clinical signs and the electrocardiogram were observed during and after infusion. Serum citrate and ionized calcium levels were also measured. RESULTS: Although the mean citrate level increased in accordance with the infusion rate, the calcium level decreased. No significant changes in clinical signs or the electrocardiogram were observed during infusion at 0.33mmol/kg/h despite an increase in the serum citrate level to 1.22+/-0.11mmol/l (pre-infusion value: 0.38+/-0.01mmol/l) and a decrease in the serum calcium level to 1.28+/-0.03mmol/l (pre-infusion value: 1.50+/-0.05mmol/l). Vomiting and QTc prolongation were observed at 0.67mmol/kg/h or higher. Salivation and tachycardia were observed at 1.33mmol/kg/h. CONCLUSIONS: Based on clinical signs and the electrocardiogram, the tolerable infusion rate of citrate in conscious dogs is concluded to be 0.33mmol/kg/h.

Animals↗
PubMed2004

Subacute toxicity and toxicokinetics of CJ-10882, a type IV phosphodiesterase inhibitor, after 4-week repeated oral administration in dogs.

The subacute toxicity and toxicokinetics of a type IV phosphodiesterase inhibitor, CJ-10882, were evaluated after single (on the 1st day) and 4-week (on the 27th day) oral administration of the drug, in doses of 0 (to serve as a control), 2, 10 and 50 mg/kg/day, to male and female dogs (n=3 for male and female dogs for each dose). During the test period, clinical signs, mortality, body weight, food consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weight and histopathology were examined. The 4-week repeated oral doses of CJ-10882 resulted in salivation, vomiting, and atrophy of the thymus. The absolute toxic dose was 50 mg/kg/day and the level at which no adverse effects were observed was 2 mg/kg/day for male and female dogs. There were no significant gender differences in the pharmacokinetic parameters of CJ-10882 for each dose after both single and 4-week oral administration. The pharmacokinetic parameters of CJ-10882 were dose independent after a single oral administration; the time to reach a peak plasma concentration (T(max)) and the dose-normalized area under the plasma concentration-time curve from time zero to 8 h in plasma (AUC(0-8 h)) were not significantly different among three doses. The accumulation of CJ-10882 after 4-week oral administration was not notable at the toxic dose of 50 mg/kg/day. For example, after 4-week administration, the dose-normalized AUC(0-8 h) value at 50 mg/kg/day (0.132 microg h/ml) was not significantly greater than that at 10 mg/kg/day (0.131 microg h/ml). After 4-week oral administration, the dose-normalized C(max) and AUC(0-8 h) at 50 mg/kg/day were not significantly higher and greater, respectively, than those after the single oral administration.

Administration, Oral↗
PubMed2005

Effects of deoxynivalenol (DON, vomitoxin) on in utero development in rats.

Deoxynivalenol (DON, vomitoxin), is one of the most common contaminants of cereal grains world-wide. The effects of DON on fetal development were assessed in Charles River Sprague-Dawley rats. Pregnant female rats were gavaged once daily with DON at doses of 0, 0.5, 1, 2.5, or 5 mg/kg body weight on gestation days (GD) 6-19. At cesarean section on GD 20, reproductive and developmental parameters were measured. All females survived to cesarean section. DON caused a dose-related increase in excessive salivation by the pregnant females, a reaction probably linked to the lack of emetic reflex in rats. At 5 mg/kg, feed consumption and mean body weight gain were significantly decreased throughout gestation, mean weight gain (carcass weight), and gravid uterine weight were significantly reduced, 52% of litters (12/23) were totally resorbed, the average number of early and late deaths per litter was significantly increased, average fetal body weight and crown-rump length were significantly decreased, the incidence of runts was significantly increased, and the ossification of fetal sternebrae, centra, dorsal arches, vertebrae, metatarsals, and metacarpals was significantly decreased. At 2.5 mg/kg, DON significantly decreased average fetal body weight, crown-rump length, and vertebral ossification. These effects may be secondary to maternal toxicity and the reduced size of the fetuses. The incidence of misaligned and fused sternebrae was significantly increased at 5.0 mg/kg. No adverse developmental effects were observed at 0.5 and 1.0 mg/kg. Dose-related increases in maternal liver weight-to-body weight ratios were observed in all treated groups (significant at 1, 2.5, and 5 mg/kg). The weight changes were correlated with dose-related cytoplasmic alterations of hepatocytes. The NOEL for maternal toxicity for this study is 0.5 mg/kg based on the dose-related increase in liver-body weight ratio at 1 mg/kg. The NOEL for fetal toxicity is 1 mg/kg based on the general reduction in fetal development at 2.5 and 5 mg/kg. DON is considered a teratogen at 5 mg/kg day in Sprague-Dawley rats based on the anomalous development of the sternebrae.

Animals↗
PubMed2004

Nitric oxide of the supraoptic nucleus influences the salivary secretion, sodium renal excretion, urinary volume and arterial blood pressure induced by pilocarpine.

Male Holtzman rats weighting 200-250 g were anesthetized with zoletil 50 mg/Kg (tiletamine chloridrate 125.0 mg and zolazepan chloridrate 125.0 mg) into quadriceps muscle and stainless steel cannulas were implanted into their supraoptic nucleus (SON). We investigated the effects of the injection into the supraoptic nucleus (SON) of FK 409, a nitric oxide donor, and NW-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor (NOS), on the salivary secretion, arterial blood pressure, sodium excretion and urinary volume induced by pilocarpine, which was injected into SON. The drugs were injected in 0.5 microl volume over 30-60 s. Controls was injected with a similar volume of 0.15 M NaCl. FK 409 and L-NAME were injected at doses of 20 microg/0.5 microl and 40 microg/0.5 microl respectively. The amount of saliva secretion was studied over a five-minute period after injection of pilocarpine into SON. Injection of pilocarpine (10, 20, 40, 80, 160 microg/microl) into SON produced a dose-dependent increase in salivary secretion. L-NAME was injected into SON prior to the injection of pilocarpine into SON, producing an increase in salivary secretion due to the effect of pilocarpine. FK 409 injected into SON attenuating the increase in salivary secretion induced by pilocarpine. Mean arterial pressure (MAP) increase after injections of pilocarpine into the SON. L-NAME injected into the SON prior to injection of pilocarpine into SON increased the MAP. FK 409 injected into the SON prior to pilocarpine attenuated the effect of pilocarpine on MAP. Pilocarpine (0.5 micromol/0.5 microl) injected into the SON induced an increase in sodium and urinary excretion. L-NAME injected prior to pilocarpine into the SON increased the urinary sodium excretion and urinary volume induced by pilocarpine. FK 409 injected prior to pilocarpine into the SON decreased the sodium excretion and urinary volume induced by pilocarpine. All these roles of pilocarpine depend on the release of nitric oxide into the SON. In summary the present results show: a) SON is involved in pilocarpine-induced salivation; b) that mechanism involves increase in MAP, sodium excretion and urinary volume.

Animals↗
PubMed2004

Heat acclimation affects the neuromodulatory role of AngII and nitric oxide during combined heat and hypohydration stress.

We studied the effect of heat acclimation on the neuromodulatory role of angiotensin (AngII) and nitric oxide during combined heat (39 degrees C) and hypohydration (water deprivation, -10% body weight) stress. Rats were divided into control (C), short (2d-STHA) or long (30d-LTHA) acclimation (34 degrees C) groups. AngII, 7-nitroindazole (7NI)-nNOS blocker, or both were centrally administered (5 mul, bolus) under light chloroform anesthesia prior to each experimental paradigms: (1) In vivo: measurements of skin-vasodilatation (VTsh) and salivation-cooling (STsh) thresholds, and heat endurance in conscious heat/hypohydrated stressed rats; (2) expression of AT(1) and AT(2) AngII receptors and nNOS were measured in the hypothalamus (Western blot); (3) transcript levels of the coding genes were measured using real-time PCR. A synthesis of the results shows a biphasic acclimatory profile of VTsh, STsh, and transcript levels of all studied genes, with transient up/down-regulatory changes on STHA. AngII affected the physiological integrative outcome primarily during euhydration, although AT membranal changes (except in LTHA) were confined to hypohydration. 7NI had an impact during hypohydration. Evidence is provided that AngII and 7NI modulate thermoregulation primarily via AT(1) and AT(2) receptors, with predominance of AT(2) signaling following LTHA and/or hypohydration, opposing a drop in AT(1)-mediated thresholds. The final shaping of AngII signaling depends on cross-talk between nNOS and AngII receptors at both molecular and protein levels. Hypohydration induces transcriptional responses but desensitizes AngII receptors signaling, attenuating their effect on VTsh and STsh, and abolishing the beneficial thermoregulatory effects achieved by heat acclimation. nNOS, AngII receptor-independent pathway is also implicated.

Acclimatization↗
PubMed2004

Cue reactivity in smokers: the effects of perceived cigarette availability and gender.

We examined the effects of perceived cigarette availability and gender on smoking cue reactivity. Smokers were exposed to smoking cues (smoking paraphernalia) and control cues whilst their subjective and physiological responses were measured. Perceived cigarette availability was manipulated on a between-subjects basis before cue exposure. Relative to control cues, smoking cues evoked increases in the level of skin conductance in all participants. Cigarette craving was also increased in the presence of smoking cues, but only in female participants. Perceived cigarette availability had no effect on these responses. Participants also showed salivary reactivity to smoking cues, with males showing a decrease in salivation, and females showing an increase, but only when cigarettes were perceived as unavailable. These results suggest that perceived cigarette availability may not influence craving and skin conductance reactivity to smoking cues in minimally dependent smokers who are not nicotine deprived. In addition, the present data suggest that there are important gender differences in craving reactivity to smoking cues.

Adult↗
PubMed2006

Does modification of olfacto-gustatory stimulation diminish sensory-specific satiety in humans?

UNLABELLED: Alimentary sensory pleasure is an important factor in ingestive behavior. Renewal of olfacto-gustatory pleasure by introducing new foods or through seasoning of previously consumed food might increase intake. OBJECTIVES: To explore whether sensory-specific satiety (SSS) for a food could be modulated, either by introducing a novel food or by a modification of sensory stimulation via seasoning the food just eaten. METHODS: 180 out of 242 subjects were distributed over 3 experiments involving ad libitum intake of one of 6 fresh foods (cucumber, tomato, pineapple, banana, peanut, pistachio). Blindfolded subjects reported their sensations for the foods on 3 parameters before and after intake of an olfactorily chosen food: Olfactory pleasure (OP), Specific appetite (SA) and Stimulus-Induced Salivation (SIS). EXP. 1: One chosen food was repeatedly presented orthonasally and rated before and after it was eaten. EXP. 2: A second food was olfactorily chosen and ingested after the first one. EXP. 3: The same food was offered again after seasoning. RESULTS: 2 min after ingestion, food intake was limited by SSS. OP, SA, SIS correlated with each other for eaten and non-eaten foods. OP for non-eaten foods increased (p<0.01) after ingestion of the chosen food to specific satiety. When the food just eaten was seasoned, OP increased (p<0.01) and led to additional intake (80% of first intake). CONCLUSION: A reduction in SSS after introduction of a new flavor or after seasoning an ingested food was observed. Such a reduction has not previously been reported. This could hint at how food sensory variation leads to over-consumption.

Adolescent↗
PubMed2005

Reproductive and developmental toxicity screening test of basic rubber accelerator, 1,3-di-o-tolylguanidine, in rats.

Twelve male and female rats per group were exposed to the rubber accelerator 1,3-di-o-tolylguanidine (DTG) by gavage at 0, 8, 20 or 50 mg/kg bw/day. Males were dosed for a total of 49 days beginning 14 days before mating. Females were dosed for a total of 40-49 days beginning 14 days before mating to day 3 of lactation throughout the mating and gestation period. At 50 mg/kg bw/day, deaths were observed in two males and three females. Lowered body weight gain and food consumption were noted in males at 50 mg/kg bw/day and females at 20 and 50 mg/kg bw/day. Mydriasis, decreased locomotor activity, bradypnea, prone position, tremor and/or salivation were observed in males and females at 20 and 50 mg/kg bw/day. No effects of DTG were found on the estrous cyclicity, precoital interval, copulation, fertility and gestational indices, numbers of corpora lutea and implantations, or gestation length. A significant decrease in the number, body weight and viability of offspring and increase in the incidence of fetuses with external malformations were found at 50 mg/kg bw/day. Oligodactyly, anal atresia and tail anomalies were observed. These data suggest that DTG may be teratogenic. The NOAELs of DTG for general and developmental toxicity in rats are 8 and 20 mg/kg bw/day, respectively.

Abnormalities, Drug-Induced↗
PubMed2001

Sialogogic activity in the rat of peptides analogous to [Tyr8]-substance P in which substitutions have been made in the N-terminal amino acids.

In order to elucidate the regulatory roles for salivation of amino acids in positions 1-4 of the N-terminal region of [Tyr8]-substance P (SP), the structure-sialogogic activity correlations of various synthetic octa- to undecapeptides replaced in positions 1-4 of [Tyr8]-SP with each of 19 common amino acids, one by one, and with the same sequence of the C-terminal hepatapeptide as that of [Tyr8]-SP, were studied in the submandibular glands of rats after intraperitoneal injection. Each of 19 octa-, nona-, deca- and undecapeptides with replaced amino acids and a penta- to decapeptide with the progressive elimination of the N-terminal portion were newly synthesized by the multipin peptide method. All octa- to undecapeptides replaced with each of 19 common amino acids in positions 1-4 had sialogogic activities. In 19 octa- and decapeptides in which P4 and P2 had been replaced, four and three replacements, respectively, had significantly increased secretory activities. In contrast, in 19 nonapeptides in which K3 had been replaced, none had significantly increased secretory activities. Furthermore, in 19 undecapeptides in which R1 had been replaced, most replacements had significantly increased or equipotent activities for fluid secretion. It is concluded that amino acids in the N-terminal region of various tachykinins may not need to be strictly conserved and that amino acid residues in the N-terminal portion, R1 in particular and P2, may strongly inhibit secretory activity.

Amino Acid Substitution↗
PubMed1996

The effect of clozapine on saliva flow rate: a pilot study.

This study examined the effect of clozapine on saliva flow rate. Unstimulated whole saliva was collected from 9 patients taking clozapine (dose range = 50-400 mg/day) and from 8 controls who had never used clozapine. There was no significant difference between the average saliva flow rates in the two groups (p > .10), nor was there significant correlation between saliva flow rate and daily clozapine dose (p > .10). Alternative explanations for observations or complaints of excessive salivation, drooling, or a choking feeling while taking clozapine are proposed.

Antipsychotic Agents↗