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PubMed1998

Sweet and sweetness-inducing activities of new triterpene glycosides, strogins.

In a previous study we isolated homologues of new oleanane-type triterpene glycosides from leaves of Staurogyne merguensis Kuntze and named them strogins. Strogins themselves have a sweet taste (sweet activity), which diminishes in a few minutes. Subsequent application of cold water to the mouth then elicits a sweet taste (sweetness-inducing activity). In the present study we systematically examined the properties of the sweet and sweetness-inducing activities of strogins. Strogins 1, 2 and 4 had both the sweet and sweetness-inducing activities, while strogins 3 and 5 had no activities. The sweetness-inducing activity in response to cold water lasted for 1 h for strogin 2 and 2 h for strogins 1 and 4. The sweetness-inducing activity was immediately diminished by application of gamma-cyclodextrin to the mouth after strogins were held in the mouth. It seems that the strogins were adsorbed on the gustatory receptor membranes and eliminated by inclusion activity of gamma-cyclodextrin. The structure of strogin resembles that of gymnemic acid, which has antisweet activity. There was competition between strogin 1 and gymnemic acid; treatment of the tongue with strogin 1 before application of Gymnema extract to the mouth reduced the antisweet activity. While the sweetness-inducing activity of curculin in response to water was suppressed by the presence of divalent cations such as Ca2+ or Mg2+, that of strogin was not suppressed by the divalent cations. The changes in the inactive complex between strogin and the sweet receptor site in the adaptation state into the active complex induced by cold stimulation were discussed.

Cations, Divalent↗

PubMed2004

Espins are multifunctional actin cytoskeletal regulatory proteins in the microvilli of chemosensory and mechanosensory cells.

Espins are associated with the parallel actin bundles of hair cell stereocilia and are the target of mutations that cause deafness and vestibular dysfunction in mice and humans. Here, we report that espins are also concentrated in the microvilli of a number of other sensory cells: vomeronasal organ sensory neurons, solitary chemoreceptor cells, taste cells, and Merkel cells. Moreover, we show that hair cells and these other sensory cells contain novel espin isoforms that arise from a different transcriptional start site and differ significantly from other espin isoforms in their complement of ligand-binding activities and their effects on actin polymerization. The novel espin isoforms of sensory cells bundled actin filaments with high affinity in a Ca(2+)-resistant manner, bound actin monomer via a WASP (Wiskott-Aldrich syndrome protein) homology 2 domain, bound profilin via a single proline-rich peptide, and caused a dramatic elongation of microvillus-type parallel actin bundles in transfected epithelial cells. In addition, the novel espin isoforms of sensory cells differed from other espin isoforms in that they potently inhibited actin polymerization in vitro, did not bind the Src homology 3 domain of the adapter protein insulin receptor substrate p53, and did not bind the acidic, signaling phospholipid phosphatidylinositol 4,5-bisphosphate. Thus, the espins constitute a family of multifunctional actin cytoskeletal regulatory proteins with the potential to differentially influence the organization, dimensions, dynamics, and signaling capabilities of the actin filament-rich, microvillus-type specializations that mediate sensory transduction in various mechanosensory and chemosensory cells.

Actins↗

PubMed1995

Altered conditioned taste aversion and glucose utilization in related brain nuclei of diabetic GK rats.

The impact of diabetes and especially hyperglycemia on brain glucose utilization and insulin binding are still not clear. This is probably due to the fact that most studies have been performed in streptozotocin treated rats that are highly hyperglycemia and that could have an effect per se on the brain. The aim of the present work was to measure, in vivo, glucose utilization and insulin binding in different areas of the brain of the spontaneously diabetic GK rats that present a moderate hyperglycemia. Brain insulin receptors number was not changed in the brain of GK rats. By contrast, an increased glucose utilization was present in the external plexiform and the intergranular layers of the olfactory bulbs, as well as in the amygdaloid of the GK rats. These structures are involved in conditioned taste aversion, which was found to be greatly altered in the diabetic rats. These results sustain the hypothesis of impaired neuropsychological functions in diabetic patients particularly in term of learning and memory.

Animals↗

PubMed1981

[Vagal acido- and glucoreceptors in the gastro-duodenal region (author's transl)].

Vagal sensitivity to carbohydrates (mainly glucose) and to acids (hydrochloric and acetic acids) was studied in the gastro-duodenal region of anesthetized cats. Action potentials were recorded extracellularly from the nodose ganglion by means of glass microelectrodes. Receptors responding to glucose perfusion were found at this level as well as receptors stimulated by acid perfusion. It is shown that each type of receptor was activated by only one kind of stimulus (carbohydrates and acids, respectively). These receptors must thus be considered as true glucoreceptors or acido-receptors. Being silent before activation, these two types of chemoreceptors discharged at a frequency that varied from 2 to 14 imp/s for the acido-receptors, and from 2 to 30 imp/s for the glucoreceptors. The response could be irregular or regular and might last several minutes. Its latency was short (between 1 and 20 s for both types of chemoreceptors. It was therefore supposed that they were located in the mucosa or neighboring structures. From the conduction velocities (0.8-1.2 m/s), it was concluded that fibers originating from the acido- and glucoreceptors belonged to the C type. Recording of the electromyographic activity from the gastro-duodenal region demonstrated that the gluco- and acid-receptors are involved in the regulation of motility of the gastric and duodenal regions.

Action Potentials↗

PubMed1979

Biochemical studies of taste sensation--VIII. Partial characterization of alanine-binding taste receptor sites of catfish Ictalurus punctatus using mercurials, sulfhydryl reagents, trypsin and phospholipase C.

1. Taste receptors for L-alanine in the channel catfish Ictalurus punctatus have been partially characterized. The binding activity, which is localized to a sedimentable fraction (Fraction P2), was assayed with L-[3H]alanine as the ligand. 2. Addition of HgCl2 or p-mercuribenzoate to the assay at 0.1-1 mM markedly inhibited binding. The effect was not reversible and was unaffected by increased L-alanine in the binding assay. 3. The sulfhydryl reagents iodoacetate, 5,5'-dithiobis(2-nitrobenzoic acid), arsenite, and N-ethylmaleimide did not show appreciable inhibition of binding. The results suggest that the inhibitory effect of mercurials is not on specific sulfhydryl groups at alanine-binding sites. 4. Treatment of Fraction P2 with phospholipase C decreased binding activity and treatment with trypsin led to increased binding activity.

Alanine↗

PubMed2006

Secretory cells of the airway express molecules of the chemoreceptive cascade.

Airway secretion is maintained by specialized non-ciliated epithelial cells whose phenotype varies with their topographical location. In addition, specialized epithelial cells located in the airway contain the molecular machinery of chemoreceptive elements. Our aim has been to evaluate whether the secretory cells themselves possess a chemoreceptive capability, which requires the simultaneous presence of chemosensory and secretory mechanisms. We performed immunohistochemical analysis with antibodies against the Clara-cell-specific secretory proteins, CC10 and CC26, as secretory markers. As chemoreceptive markers, we employed antibodies against alpha-gustducin and phospholipase C beta 2 (PLCbeta2), two components of the taste transduction pathway. We also attempted to characterize further the secretory cell type by using a marker of chloride secretion, cystic fibrosis transmembrane regulator (CFTR). We found alpha-gustducin localized in non-ciliated cells of the epithelium lining the trachea and bronchioles of adult rats, where it was also co-expressed with CC10 and CC26. Ultrastructural immunohistochemistry revealed alpha-gustducin in the apical cytoplasm of secretory cells, concentrated around and inside the granules. CFTR was also observed in a subpopulation of non-ciliated epithelial cells, co-localized with some alpha-gustducin- and PLCbeta2-immunoreactive cells, at all levels of the airway epithelium. We conclude that non-ciliated epithelial cells of the rat airway express components of distinct signaling mechanisms and suggest that secretory events are driven by a molecular mechanism activated by the binding of luminal substances to G-protein-coupled receptors.

Animals↗

PubMed1993

[Stability and new formulations of hexetidine. 2. Formulations and in vitro bioavailability].

The solubilization of the water insoluble antimicrobial compound hexetidine is achieved by tensides and cyclodextrins. Using tensides the active ingredient is associated with the lipophilic part of the emulsifier. Tensides with a hydrophilic element in the lipophilic part of the molecule show better solubilizing properties. In contrast a higher stability is achieved with emulsifiers without hydrophilic elements in the lipophilic part of the molecule. The antimicrobial activity, determined by an in vitro test, is not influenced by the type of emulsifier. Cyclodextrins form inclusion complexes with hexetidine. Hydroxy propyl-beta-cyclodextrin is preferred due to its high water solubility. This inclusion complex shows compared with tenside solubilization a better taste and stability. The in vitro antimicrobial activity was comparable to tenside solubilized products.

Bacteria↗

PubMed2002

Behavioural pharmacology of octopamine, tyramine and dopamine in honey bees.

In the honey bee, responsiveness to sucrose correlates with many behavioural parameters such as age of first foraging, foraging role and learning. Sucrose responsiveness can be measured using the proboscis extension response (PER) by applying sucrose solutions of increasing concentrations to the antenna of a bee. We tested whether the biogenic amines octopamine, tyramine and dopamine, and the dopamine receptor agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN) can modulate sucrose responsiveness. The compounds were either injected into the thorax or fed in sucrose solution to compare different methods of application. Injection and feeding of tyramine or octopamine significantly increased sucrose responsiveness. Dopamine decreased sucrose responsiveness when injected into the thorax. Feeding of dopamine had no effect. Injection of 6,7-ADTN into the thorax and feeding of 6,7-ADTN reduced sucrose responsiveness significantly. These data demonstrate that sucrose responsiveness in honey bees can be modulated by biogenic amines, which has far reaching consequences for other types of behaviour in this insect.

Adrenergic alpha-Agonists↗

PubMed2001

Bitter taste transduced by PLC-beta(2)-dependent rise in IP(3) and alpha-gustducin-dependent fall in cyclic nucleotides.

Current evidence points to the existence of multiple processes for bitter taste transduction. Previous work demonstrated involvement of the polyphosphoinositide system and an alpha-gustducin (Galpha(gust))-mediated stimulation of phosphodiesterase in bitter taste transduction. Additionally, a taste-enriched G protein gamma-subunit, Ggamma(13), colocalizes with Galpha(gust) and mediates the denatonium-stimulated production of inositol 1,4,5-trisphosphate (IP(3)). Using quench-flow techniques, we show here that the bitter stimuli, denatonium and strychnine, induce rapid (50-100 ms) and transient reductions in cAMP and cGMP and increases in IP(3) in murine taste tissue. This decrease of cyclic nucleotides is inhibited by Galpha(gust) antibodies, whereas the increase in IP(3) is not affected by antibodies to Galpha(gust). IP(3) production is inhibited by antibodies specific to phospholipase C-beta(2) (PLC-beta(2)), a PLC isoform known to be activated by Gbetagamma-subunits. Antibodies to PLC-beta(3) or to PLC-beta(4) were without effect. These data suggest a transduction mechanism for bitter taste involving the rapid and transient metabolism of dual second messenger systems, both mediated through a taste cell G protein, likely composed of Galpha(gust)/beta/gamma(13), with both systems being simultaneously activated in the same bitter-sensitive taste receptor cell.

Animals↗

PubMed2005

Delta9-THC induced hyperphagia and tolerance assessment: interactions between the CB1 receptor agonist delta9-THC and the CB1 receptor antagonist SR-141716 (rimonabant) in rats.

This study examined effects of the CB1 receptor antagonist/inverse agonist SR-141716 and the CB1 receptor agonist delta9-tetrahydrocannabinol (delta9-THC) on feeding behavior in male Sprague-Dawley rats. Rats were housed individually with free access to regular pelletized laboratory chow [after a 2 weeks handling phase, animals had access to regular chow for 21 h (Study 1) or 22 h (Study 2); high-fat powder food for 3 h in Study 1 and 2 h in Study 2, respectively], and free access to water. Animals were maintained on a reversed 12-h light/dark cycle (dark beginning at noon). Rats were habituated to this type of feeding and light/dark schedule for 3 weeks until a stable baseline for food intake was achieved. In Study 1, animals were examined after administration of delta9-THC alone (dose range 0.1-1.8 mg/kg), SR-141716 alone (dose range 0.03-0.3 mg/kg), and the two drugs combined; injections were given i.p. at the beginning of the second hour after presenting the high-fat diet and drugs were given twice weekly. There was a dose-related increase in high-fat diet intake, peaking at 0.56-1 mg/kg delta9-THC. SR-141716 alone suppressed the high-fat diet intake below control levels. A combination of 0.3 mg/kg SR-141716 and 0.56 mg/kg delta9-THC counteracted the effects on consumption of either drug alone. In Study 2, experimental rats were treated initially with 0.56 mg/kg delta9-THC for six consecutive days; controls received vehicle. Attenuation of the hyperphagia (high-fat diet) was evident after the second injection. Increasing doses of delta9-THC (1 and 1.8 mg/kg, for two and three consecutive days, respectively) did not reinstate the initial hyperphagia. In conclusion, low-to-moderate doses of delta9-THC produced hyperphagia (to a high-fat food source), which was antagonized by SR-141716. SR-141716 singly suppressed intake of the high-fat diet. Delta9-THC-induced hyperphagia dissipated rapidly upon chronic treatment; however, it is unclear whether this reflects pharmacological tolerance or the emergence of a conditioned taste aversion in Study 2.

Analysis of Variance↗

PubMed2006

Antagonistic sensory cues generate gustatory plasticity in Caenorhabditis elegans.

Caenorhabditis elegans shows chemoattraction to 0.1-200 mM NaCl, avoidance of higher NaCl concentrations, and avoidance of otherwise attractive NaCl concentrations after prolonged exposure to NaCl (gustatory plasticity). Previous studies have shown that the ASE and ASH sensory neurons primarily mediate attraction and avoidance of NaCl, respectively. Here we show that balances between at least four sensory cell types, ASE, ASI, ASH, ADF and perhaps ADL, modulate the response to NaCl. Our results suggest that two NaCl-attraction signalling pathways exist, one of which uses Ca(2+)/cGMP signalling. In addition, we provide evidence that attraction to NaCl is antagonised by G-protein signalling in the ASH neurons, which is desensitised by the G-protein-coupled receptor kinase GRK-2. Finally, the response to NaCl is modulated by G-protein signalling in the ASI and ADF neurons, a second G-protein pathway in ASH and cGMP signalling in neurons exposed to the body fluid.

Animals↗

PubMed2006

Gender specific effects of ethanol in mice, lacking CCK2 receptors.

Neuropeptide cholecystokinin (CCK) has been reported to suppress ethanol intake, but there is contradictory evidence about the role of CCK(2) receptors. In the present study anxiolytic, hypolocomotor and sedative effects of acute ethanol administration, but also voluntary ethanol consumption were studied in male and female mice, lacking CCK(2) receptors (-/-). Ethanol (1.0 and 2.0 g/kg) induced a significant reduction of anxiety-related behaviours in the elevated plus-maze, but this effect was statistically significant only in female homozygous mice (-/-). In male mice, lacking CCK(2) receptors (-/-), but not in their wild-type littermates (+/+), the suppression of vertical locomotor activity was caused by ethanol at a dose 0.5 g/kg. The highest dose of ethanol (2.0 g/kg) produced statistically significant reduction of horizontal locomotor activity only in female wild-type (+/+) mice, but this effect was related to increased basal activity when compared to female mutant (-/-) mice. Duration of the loss of righting reflex was not significantly affected by genotype or gender, but blood ethanol levels at regain of righting reflex were significantly lower in female homozygous mice (-/-) compared to their wild-type (+/+) littermates, indicating increased sensitivity to the sedative effect of ethanol. Ethanol intake, but not preference, at concentration 10% was significantly increased in female mice, lacking CCK(2) receptors (-/-). The present study revealed an altered response to the acute effects of ethanol in CCK(2) receptor deficient mice (-/-). These changes are gender-specific and could be attributed to the altered activity of dopaminergic system in male mice and increased activity of GABA-ergic system in female mice as established in our previous studies.

Alcohol Drinking↗

PubMed1982

Pulmonary and respiratory tract receptors.

Nervous receptors in the lungs and respiratory tract can be grouped into four general categories. 1. Deep, slowly adapting end-organs, which respond to stretch of the airway wall and have large-diameter myelinated fibres; those in the lungs are responsible for the Breuer-Hering reflex. 2. Endings in and under the epithelium which respond to a variety of chemical and mechanical stimuli (i.e. are polymodal), usually with a rapidly adapting discharge, and with small-diameter myelinated fibres; they are responsible for defensive reflexes such as cough and sneeze, and for the reflex actions to inhaled irritants and to some respiratory disease processes. 3. Receptors with nonmyelinated nerve fibres which, being polymodal, are stimulated by tissue damage and oedema and by the mediators released in these conditions; these receptors may be similar in function to 'nociceptors' in other viscera, and set up appropriate reflexes as a reaction to respiratory damage. 4. Specialized receptors such as those for taste and swallowing, and those around joints and in skeletal muscle. Stimulation of any group of receptors may cause reflex changes in breathing (including defensive reflexes), bronchomotor tone, airway mucus secretion, the cardiovascular system (including the vascular bed of the airways), laryngeal calibre, spinal reflexes and sensation. The total pattern of motor responses is unique for each group of receptors, although it is probably unusual for one type of receptor to be stimulated in isolation. The variety of patterns of motor responses must reflect the complexity of brainstem organization of these systems.

Animals↗

PubMed1978

Liquid-sensitive laryngeal receptors in the developing sheep, cat and monkey.

1. Action potentials were recorded from single afferent units of the superior laryngeal nerves in neonatal and adult sheep, cats and monkeys when liquids were passed over the laryngeal mucosa. 2. Two types of mucosal receptors, sensitive to water but not to isotonic saline, were found in each species from birth. The most common type of unit responded after a short latency (less than 1 sec), discharged maximally in the first 1-3 sec and became inactive when the stimulus was withdrawn. The other type responded only after several seconds, the discharges gradually increasing in frequency and continuing after removal of the stimulus. 3. Reproducible responses were elicited by tactile stimulation of the laryngeal mucosa over the receptive field of each of the long-latency units. Fewer than 50% of the short-latency units were excited, the remainder responding only unreproducibly to firm pressure. 4. Short-latency, but not long-latency, units responded to milks, gastric contents, saliva and isotonic solutions of sugars. 5. The responses of long-latency units to water were often modified by, but rarely dependent on, reflexly evoked activity in laryngeal muscles. 6. The conduction velocities of afferent fibres of water sensitive units ranged from 22 to 49 m/sec, and differed little from those of water-insensitive laryngeal mechanoreceptors. 7. Histological examination of the laryngeal mucosa showed that taste buds were present in lambs from birth whereas they developed post-natally in kittens and monkeys. The evidence suggests that taste buds were not associated with water-sensitive units.

Action Potentials↗

PubMed1995

The intensity of a fetal taste aversion is modulated by the anesthesia used during conditioning.

Rat fetuses (E18) can learn a taste aversion in utero if experience with a sweet flavor (saccharin = Sac) is followed by a malaise-producing injection of lithium chloride (LiCl). Here we report that this phenomenon can be significantly modulated by the type of anesthesia administered to the pregnant dam before the conditioning procedure. Dams were anesthetized with one of the following drugs or drug combinations: (1) sodium pentobarbital; (2) ketamine hydrochloride and xylazine; or (3) sodium pentobarbital and ketamine hydrochloride. While under the influence of these anesthetics, rat fetuses received pairings of Sac + LiCl or one of the following sets of oral and systemic (i.p.) control injections: Sac + Saline, H2O + LiCl; H2O + Saline. At age 15 days neonatal rats were given a taste preference test by allowing them to select nipples painted with either saccharin or vehicle (H2O). After weaning, rats were given an additional taste preference test where they were allowed to drink from bottles filled with either 0.30% saccharin or water. Neonates that received Sac + LiCl injections avoided saccharin-painted nipples while neonates that received control injections in utero preferred saccharin-painted nipples. Rats that acquired the taste aversion under the influence of ketamine showed a significantly stronger conditioned taste aversion on the nipple preference test than did those from dams injected with sodium pentobarbital. The conditioned taste aversion was not detectable later during the bottle preference test. Since ketamine blocks N-methyl-D-aspartate (NMDA) glutamate receptors, and these receptors have been implicated in neural plasticity during development, our data suggest that NMDA antagonism can potentiate fetal learning. Ketamine has been used as an obstetrical and pediatric anesthetic.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthetics↗

PubMed2006

Candesartan cilexetil in children with hypertension or proteinuria: preliminary data.

The angiotensin II receptor blockers irbesartan and losartan effectively reduce blood pressure and proteinuria in childhood. We were impressed by the neutral taste and the small size of the candesartan cilexetil tablets. This angiotensin II receptor blocker was used during 4 months in 17 pediatric patients (aged 0.5-16, median 4.5 years) with chronic arterial hypertension (n=6), overt proteinuria (n=2), or both (n=9). The initial candesartan dose of 0.23 (0.16-0.28) mg/kg body weight once daily (median and interquartile ranged) was doubled in ten patients [final dose 0.35 (0.22-0.47) mg/kg body weight]. No adverse clinical experiences were noted on candesartan. Candesartan increased plasma potassium by 0.3 (0.0-0.8) mmol/l (P<0.01). In children with arterial hypertension, blood pressure decreased by 9 (3-13)/9 (3-18) mmHg (P<0.01); in those with overt proteinuria the urinary albumin/creatinine ratio decreased by 279 (33-652) mg/mmol (P<0.05). In conclusion, in children candesartan reduces blood pressure and proteinuria with an excellent short-term tolerability profile.

Adolescent↗

PubMed2003

Differential gurmarin suppression of sweet taste responses in rat solitary nucleus neurons.

We examined the effect of the sweet transduction blocker gurmarin on taste responses recorded from neurons in the rat solitary nucleus (NST) to determine how gurmarin sensitivity is distributed across neuronal type. Initially, responses evoked by washing the anterior tongue and palate with 0.5 M sucrose, 0.1 M NaCl, 0.01 M HCl, and 0.01 M quinine-HCl were recorded from 35 neurons. For some cells, responses to a sucrose concentration series (0.01-1.0 M) or an array of sweet-tasting compounds were also measured. Gurmarin (10 microg/ml, 2-4 ml) was then applied to the tongue and palate. Stimuli were reapplied after 10-15 min. Neurons were segregated into groups based on similarities among their initial response profiles using hierarchical cluster analysis (HCA). Results indicated that sucrose responses recorded from neurons representative of each HCA-defined class were suppressed by gurmarin. However, a disproportionate percentage of cells in each group displayed sucrose responses that were substantially attenuated after gurmarin treatment. Postgurmarin sucrose responses recorded from neurons that composed 57% of class S, 40% of class N, and 33% of class H were suppressed by >or=50% relative to control. On average, attenuation was statistically significant only in class S and N neurons. Although the magnitude of gurmarin-induced response suppression did not differ across sucrose concentration, responses to different sweet-tasting compounds were differentially affected. Responses to NaCl, HCl, or quinine were not suppressed by gurmarin. Results suggest that information from gurmarin-sensitive and -insensitive receptor processes converges onto single NST neurons.

Action Potentials↗

PubMed2002

In vivo effects of intracortical administration of NMDA and metabotropic glutamate receptors antagonists on neocortical long-term potentiation and conditioned taste aversion.

It has been proposed that long-term potentiation (LTP), a form of activity-dependent modification of synaptic efficacy, may be a synaptic mechanism for certain types of learning. Recent studies on the insular cortex (IC), a region of the temporal cortex implicated in the acquisition and storage of conditioned taste aversion (CTA), have demonstrated that tetanic stimulation of the basolateral nucleus of the amygdala (Bla) induce an N-methyl-D-aspartate (NMDA) dependent LTP in the IC of adult rats in vivo. Here we present experimental data showing that intracortical administration of the NMDA receptor competitive antagonists CPP (-3(-2 carboxipiperazin-4-yl)-propyl-1-phosphonic acid, 0.03 microg per hemisphere) and AP-5 (D(-)-2-amino-5-phosphonopentanoic, 2.5 microg per hemisphere) disrupt the acquisition of conditioned taste aversion, as well as IC-LTP induction in vivo. In contrast, administration of the metabotropic glutamate receptor antagonist MCPG ((RS)-alpha-methyl-4-carboxyphenylglycine, 2.5 microg per hemisphere) does not disrupt the acquisition of CTA nor IC-LTP induction. These findings are of particular interest since they provide support for the view that the neural mechanisms underlying NMDA-dependent neocortical LTP constitute a possible mechanism for the learning-related functions performed by the IC.

2-Amino-5-phosphonovalerate↗