Age-related changes in the antinociception induced by taurine in mice.

Taurine is a nonessential amino acid that is of medical interest for the nutrition of infants. Taurine has been found in the central nervous system of rodents and humans, and among its potential therapeutic uses, it is interesting to remark its analgesic actions. It is also well known that concentration levels during the fetal and prenatal periods are higher than in adulthood. The data obtained so far indicate that taurine is involved in the development process of the brain and possibly other organs. The taurine levels in old age are still unknown, but it is presumed that they will be different from those of younger animals. Data about age-related alterations and functional modifications of this and other amino acids are still scarce. The aim of the present work was to study the antinociceptive effect of taurine and its relationship with aging in mice. No differences were found between prepubertal and young adult animals; on the contrary, old animals showed significantly reduced sensitivity to the antinociception induced by taurine; in fact, at the tested doses, taurine did not induce antinociception in this group of mice. The mechanism underlying this effect has not been clarified because there are several mechanisms and neurotransmitter systems involved in the antinociception induced by taurine.

Role of K+ -channels in homotaurine-induced analgesia.

In previous articles, antinociceptive activity for homotaurine has been demonstrated to be mediated by opioid, GABAergic and cholinergic mechanisms. GABAB-agonists affect K+-channels and it is known that K+-channels modulate specific activation of opioid receptors. In this study, we examined the involvement of K+-channels in the antinociceptive activity of homotaurine (22-445 mg/kg). Antinociceptive response was obtained after icv pretreatment with the channel specific blockers 4-aminopyridine (voltage-dependent channels), tetraethylammonium (Ca++ and voltage-dependent) and gliquidone (ATP-dependent). The nociceptive tests performed were acetic acid induced abdominal constriction (mice) and tail flick (rats) tests. Acetic acid responses to homotaurine were inhibited by tetraethylammonium (5 microg) and gliquidone (16 microg). Tail flick response to homotaurine was inhibited by tetraethylammonium (50 microg), gliquidone (40 and 80 microg) and 4-aminopyridine (25 and 250 ng). These results suggest an involvement of the three types of K+-channels in antinociception by homotaurine, depending on specific homotaurine and blocker doses. At a spinal level, they appear to be involved together with GABAB and opioid mechanisms. Peripherally, only tetraethylammonium channels would be substantially activated during homotaurine antinociceptive effect.

GABA(B) receptors and opioid mechanisms involved in homotaurine-induced analgesia.

1. The involvement of GABA(B) receptors and opioid mechanisms in homotaurine-induced analgesia has been investigated in current models of nociception by using a GABA(B) receptor antagonist, morphine, and naloxone. CGP 35348 (50-200 mg/kg IP), a highly selective GABA(B) antagonist, was administered prior to carrying out a dose-response curve of homotaurine (22.6-445 mg/kg IP) antinociceptive effect in the abdominal constriction (mice) and tail flick (rats) tests. 2. The tail flick test was performed in animals pretreated with morphine (0.5 mg/kg SC) and naloxone (1 mg/kg), 15 min before amino acid. Animals treated with saline 10 ml/kg (mice) or 1.25 ml/kg (rats) were included as control for the vehicle used. 3. CGP 35348 antagonized the antinociceptive effect of homotaurine in both tests. The range of doses affected by the interaction depended on the test assayed, but it was coincident for the main part of the dose-response curve. 4. A subanalgesic dose of morphine potentiated the antinociceptive effect of lower doses of homotaurine in the tail flick test. Naloxone pretreatment inhibited the antinociceptive effect of homotaurine. 5. These data imply that GABA(B) receptor subpopulations and opiate mechanisms are involved in the antinociceptive effect of homotaurine. Because functional relationships have been found between GABAergic and opiate systems in analgesic effects, an interaction of the two mechanisms may be operating in the effects described for homotaurine.

Implication of beta 1- and beta 2-adrenergic receptors in the antinociceptive effect of tricyclic antidepressants.

Tricyclic antidepressants have been shown to be useful for the treatment of pain of varying etiology. Monoaminergic systems seem to be implicated in this phenomenon. In this study, the influence of the selective beta 1- (CGP 20712A) and beta 2- (ICI 118551) adrenergic blockers on the antinociceptive effect of desipramine and nortriptyline was studied in mice using physical and chemical nociceptive tests that implicate different levels of sensory-motor integration in the central nervous system (CNS). An activity test was performed to detect "false positive" or "false negative" results. Results obtained show that both CGP 20712A and ICI 118551 are able to antagonize the antinociceptive effect of these antidepressants in physical tests (hot-plate and tail-flick). However, in chemical tests (acetic acid and formalin), the analgesic effect of the antidepressants used was only antagonized by CGP 20712A. These results suggest that the analgesic effect of desipramine and nortriptyline is mediated by beta-adrenoceptors. The beta-adrenoceptor involved depends on the type of nociceptive stimulus: beta 1 and beta 2 are both implicated when the stimulus is physical, but only beta 1 is involved when the stimulus is chemical.

A possible interaction of potential clinical interest between digoxin and acarbose.

This case report describes a 69-year-old woman with diabetes mellitus and heart failure who repeatedly had unusual subtherapeutic levels of plasma digoxin. When the drug therapeutic regimen was checked it was found that a new drug, acarbose, had been added to the therapeutic regimen before the unexpected laboratory reported results. Because other drugs included in her therapeutic menu were rejected as being responsible for decreased levels of digoxin, it was recommended to discontinue acarbose to evaluate its role. In the absence of acarbose, the plasma concentration of digoxin increased to the therapeutic range. We concluded that acarbose may be responsible for a pharmacokinetic interaction with digoxin by a still unknown mechanism. Although discontinuation of acarbose was recommended, the attending physician discontinued administration of digoxin because the clinical condition of the patient did not get worse during subtherapeutic levels of digoxin.

Synthesis and analgesic activity of 2-amino-5-tert-butyl-2-oxazoline.

2-Amino-5-tert-butyl-2-oxazoline (ATBO, 2) was synthetized from 3,3-dimethyl-2-iodobutyl isocyanate via N-(3,3-dimethyl-2-iodobutyl) urea (1). The structures of compounds 1 and 2 are based on analytical and spectroscopic data. Compound 2 induced in rats and mice a peripheral antinociceptive effect through both spinal and supraspinal mechanisms. ATBO did not impair motor coordination or activity of the experimental animals.

Role of GABAA and GABAB receptors and peripheral cholinergic mechanisms in the antinociceptive action of taurine.

1. Gabaergic and cholinergic mediation in the antinociceptive effect of taurine has been investigated in mice (acetic acid test) and rats (tail-flick test). 2. Scopolamine sulfate and methylnitrate exhibit intrinsic antinociceptive activity and increase the effect of taurine in mice. 3. Baclofen also increases the antinociceptive effect of taurine in mice. 4. Anticholinergic agents and bicuculline but not CGP 35348 antagonize the effect of taurine in rats. 5. These results suggest that the antinociceptive effect of taurine may be partly mediated by spinal GABAA receptors and peripheral cholinergic mechanisms.

Effects of morphine on isolated right atria of the rat.

1. The present study describes the effects of morphine in the absence or presence of naloxone or atropine in the isolated right atria of the rat. 2. Morphine significantly decreased the auricular chronotropism. 3. The maximal effect was 10 +/- 1.0%. 4. Similar results were obtained in reserpinized animals (13 +/- 0.2% maximum). 5. Naloxone (5 x 10(-7) or 5 x 10(-6) M) did not change the inhibitory effects induced by morphine. 6. The maximal effect obtained with morphine in the presence of atropine (5 x 10(-7) M) was 9 +/- 0.1% similar to that obtained with morphine alone. 7. These results suggest that opioid or vagal mechanisms may not be involved in the cardiac inhibitory effects induced by morphine.

GABAergic and cholinergic mediation in the antinociceptive action of homotaurine.

1. The role of GABAergic and cholinergic mechanisms in the antinociceptive effect of homotaurine (22.25-111.24 mg/kg i.p.) in chemical (acetic acid) and thermal (tail flick, tail immersion) tests has been studied by means of the interaction with baclofen and anticholinergic drugs. 2. Baclofen (2 mg/kg p.o.) and scopolamine sulfate (2.5 mg/kg i.p.) potentiate the antinociceptive effect of the amino acid in the chemical test. 3. Bicuculline (1 mg/kg i.p.) pretreatment does not modify the antinociceptive effect of homotaurine in the tail immersion and tail flick tests. 4. Scopolamine sulfate and methylnitrate (1 mg/kg i.p.) antagonise the effect of homotaurine (111.24 mg/kg i.p.) in the tail flick test. 5. The above results imply that peripheral GABAB and central cholinergic mechanisms play a role in the antinociceptive effect of homotaurine.

Factors affecting gene expression of patatin and proteinase-inhibitor-II gene families in detached potato leaves: : Implications for their co-expression in developing tubers.

In whole intact potato (Solanum tuberosum L.) plants, the gene families of class-I patatin and proteinase inhibitor II (Pin 2) are constitutively expressed in the tubers. However, they are also induced in detached potato leaves in the presence of light. To further characterize this light action, the detached leaves were subjected to monochromatic light of different wavelengths and to darkness in the presence of metabolites and inhibitors. Patatin genes could be induced by the simultaneous application of sucrose (sugars) and glutamine in darkness. Neither of these metabolites was active when supplied alone. When photosynthesis was blocked by 3-(3,4-Di-chlorophenyl)-1, 1-dimethylurea (DCMU) in the light, patatin genes were not expressed; however, the inhibition was overcome in the presence of sucrose. This indicates that besides its role in photosynthetic carbohydrate production, light may be essential for the supply of amino acids (or reduced nitrogen). Unlike patatin, Pin 2 genes were, to a small extent, also active in darkness, and sucrose weakly enhanced this expression. However, DCMU did not affect Pin 2 expression in the light. Both abscisic acid and methyl jasmonate strongly promoted the accumulation of Pin 2 mRNA independent of the light conditions, indicating that the gene family is probably under hormonal control. The phytohormones did not affect patatin gene expression. Inhibitors of cytosolic (cycloheximide) and organellar (chloramphenicol) translation had opposite effects on the two gene families. Careful evaluation of the inhibitors' action indicates that protein synthesis (cytosol) is required for the expression of Pin 2 genes but not for the patatin genes. These results clearly demonstrate that, although in situ both gene families are constitutively expressed in the same plant organ (tuber) in intact plants, their expression is mediated by different factors.

Total and free valproic acid: plasma level/dose ratio in monotherapy.

Free plasma level/dose ratio of valproic acid (L/D-F) can be more effective than total plasma level/dose ratio (L/D-T) in adjusting dosage regimens. The influence of age, dose, and plasma concentration have been studied on L/D-T and L/D-F ratios. L/D-T and L/D-F ratios from 67 outpatients under long-term monotherapy were obtained. Analytical data was carried out by fluorescent polarized immunoassay. L/D-T and L/D-F ratios do not vary according to age. L/D-T and L/D-F ratios decreased while the dosage increased; both ratios increased with an increase in total plasma level of valproic acid. Significant differences were found between L/D-T and L/D-F ratios. Dose and interindividual variations are the factors which most influence L/D ratios of valproic acid.

Evidence for involvement of catecholamines in the effect of morphine on ventricular automaticity in the rat.

1. The present study examined the effects of morphine on ectopic automaticity induced by local injury in the isolated right ventricle of the rat. 2. Morphine (10(-7)-5 x 10(-5) M) induced a significant increase of ventricular rate similar to that produced by noradrenaline. The excitatory effect of morphine was not modified by the presence of naloxone (5 x 10(-5) M). The maximal effect obtained with morphine in the presence of naloxone was 60 +/- 7%, similar to that obtained with morphine alone (67 +/- 15%). The EC50 values for morphine in the absence (0.89 x 10(-7) M) and presence of naloxone (0.87 x 10(-7) M) were also similar. Apparently this effect is not mediated by postsynaptic opioid receptors. 3. The ventricular automaticity induced in isolated right ventricle of the rat was significantly decreased by the highest concentrations of naloxone (5 x 10(-5) and 10(-7) M). 4. Morphine (10(-9)-5 x 10(-5) M) did not significantly change ventricular automaticity in the presence of propranolol (5 x 10(-8) M) or in reserpinized rats (5 mg kg-1 i.p. 24 h before the experiments). The maximal increases induced by morphine in the presence of propranolol or in reserpinized rats were 5 +/- 0.8% and 16 +/- 14.7% respectively. These results were significantly different from the maximal increase obtained without propranolol or with non-reserpinized animals. It is possible that the effects of morphine on ventricular automaticity could be mediated by an indirect effect located presynaptically at the adrenergic nerve terminals through the release of catecholamines.

Opioid and prostaglandin mechanisms involved in the effects of GABAergic drugs on body temperature.

1. Intraperitoneal (i.p.) injection to restrained rats of GABA (250-1000 mg/kg) or the GABAA-receptor agonist muscimol (0.05-1 mg/kg) induced a dose-dependent decrease in body temperature (BT). 2. Intraperitoneal injection of low doses of the GABAB-receptor agonist (+/-)-baclofen (1-10 mg/kg) did not significantly affect BT. However, baclofen, at high doses (30 mg/kg), produced an increase in BT. 3. Pretreatment with either bicuculline (3 mg/kg) or naloxone (1 mg/kg) did not significantly modify the hypothermic response observed with GABA or muscimol, except for the high dose of GABA (1000 mg/kg) which was potentiated by bicuculline pretreatment. 4. Indomethacin pretreatment (5 mg/kg) significantly antagonized the hypothermia induced by GABA and muscimol. 5. Injection of baclofen alone (1 mg/kg) did not significantly affect BT, but in presence of the GABAA antagonist bicuculline, baclofen significantly decreased BT. 6. Baclofen-induced hyperthermia appear to be via prostaglandin and opioid mechanisms since both indomethacin and naloxone abolish this effect. 7. The hypothermia induced by GABA-agonists appears to be due to simultaneous activation of GABAA and GABAB receptors, while the hyperthermic effect of baclofen appears to be due to stimulation of GABAB receptors. 8. The present results suggest that involvement of prostaglandins in the effects of GABA, muscimol and baclofen, while endogenous opiates seem to be implicated only in baclofen induced hyperthermia. 9. It can be concluded that GABA may be involved in the control of BT through GABAA and GABAB receptors.

Effect of homotaurine in experimental analgesia tests.

1. The possible antinociceptive action of GABA A receptor agonist homotaurine, has been studied through a battery of chemical (acetic acid) and thermal (hot plate, tail flick and tail immersion) tests in rats and mice. 2. The aminoacid was used at the following doses 22.25; 55.62 and 111.24 mg/kg i.p. and 50-100 micrograms i.c.v.; and measurements were made at the time of and at 5, 15 and 30 min after drug administration. 3. Homotaurine exhibited a significantly antinociceptive effect in all the above mentioned test except hot plate and when administered i.c.v. in the tail flick test. 4. The antinociceptive effect in the chemical test was dose and time dependent. 5. In the tail immersion test, latency time for withdrawal of the tail was significantly increased with the dose of 55.62 mg/kg at 15 min and 111.24 mg/kg at 30 min. 6. In the tail flick test the antinociceptive effect was dose dependent at 15 and 30 min. 7. From the above results the implication of peripheral and spinal mechanisms in the antinociceptive effect of homotaurine may be concluded.

Antinociceptive effect of taurine and its inhibition by naxolone.

1. We have tested the effect of taurine on nociceptive stimulation provoked by chemical agent (acetic acid) and by the hot-plate test. 2. In the acetic acid test, taurine exerts an antinociceptive effect at every dose and time assayed. The observed effect was dose-related. 3. Naxolone pretreatment antagonizes the antinociceptive effect of taurine in the acetic acid test. 4. The results obtained in hot-plate test show that taurine did not significantly affect latency time for paw licking.

Phenobarbital plasma level/dose ratio in monotherapy. Influence of age, sex and dose.

Phenobarbital plasma level/dose ratio (L/D) has been studied in 536 outpatients distributed in groups according to age, sex and drug dosage. Samples were obtained prior to the first morning dose. Plasma levels that correspond to the steady-state phase were determined by homogeneous enzymatic immunoassay (EMITR). From the results it must be pointed out: 1) An increase of L/D as the age increases within each group; 2) A decrease of L/D as the dose of phenobarbital increases in the overall sample; 3) Sex does not affect L/D in any of the subgroups studied; 4) For a given dose higher blood levels are reached in children 7 to 15 years old in our sample than in other comparable studies in Spain.

Effect of PK 11195, an antagonist of benzodiazepine receptors, on platelet aggregation in a model of anxiety in the rat.

1. Anxiety induced by forced swimming increases maximal intensity (h) of platelet aggregation (PAG) and time to reach it (t). 2. PK 11195 pretreatment (12.5 and 25 mg/kg) reverses anxiety-induced PAG changes. At 6.25 mg/kg it inhibits PAG. 3. Changes induced by anxiety on PAG may be mediated by peripheral-benzodiazepine receptors.

Effect of low-dose aspirin treatment on human platelet aggregation.

1. The effect of aspirin 50 mg/day during 28 days on human platelet aggregation (PAG) induced by ADP and collagen has been studied in 12 healthy volunteers. 2. The results show that aspirin treatment reduces both ADP and collagen-induced PAG (P less than 0.01). 3. Maximal inhibition of PAG appears in the second week of treatment for ADP-induced PAG (41.1%) and in the fourth week for collagen-induced PAG (50.2%). No significant differences exist between the controls taken along the treatment during the 28 days of the study. 4. The data suggest that the low-dose of aspirin tested provides adequate PAG inhibition to be used in the prophylaxis of thromboembolism patients, thus avoiding intolerances to higher dosages.

Hypothermic effect of GABA in conscious stressed rats: its modification by cholinergic agonists and antagonists.

gamma-Aminobutyric acid (GABA) intraperitoneally injected (i.p.) produced a dose-dependent hypothermia in restrained rats. GABA-induced hypothermia (1000 mg kg-1) was antagonized by pretreatment with atropine (2.5 and 10 mg kg-1 i.p.), hyoscine butylbromide (2.5 mg kg-1 i.p.), hexamethonium (0.75 mg kg-1 i.p.) or physostigmine (0.2 mg kg-1 s.c.). Hexamethonium (7.5 mg kg-1 i.p.) did not influence the hypothermia induced by GABA. The antagonism by physostigmine of GABA-induced hypothermia was attenuated by pretreatment of the rats with either alpha-methyl-p-tyrosine (200 mg kg-1 i.p.) or hexamethonium (7.5 mg kg-1 i.p.), but it was potentiated by either atropine (5 mg kg-1 i.p.) or hexamethonium (0.75 mg kg-1 i.p.). The data indicate that GABA-induced hypothermia may be partly mediated by acetylcholine release. Muscarinic receptors may play an important role in the effect of GABA. The results support the hypothesis of nicotinic presynaptic receptors modulating noradrenergic nerve endings that play a part in the hypothermic response of GABA.

Effects of GABA on gastric acid secretion and ulcer formation in rats.

The effects of gamma-aminobutyric acid (GABA), bicuculline and baclofen, orally and intraperitoneally (i.p.) administered, on the development of stress and pyloric ligation-induced gastric ulcers, were studied in rats. GABA, but not baclofen, significantly reduced the frequency and severity of both models as assessed by ulcer index, incidence and number of ulcers/animal. Gastric protection was dose-related in both experimental models and was completely antagonized by pretreatment with bicuculline methiodide, that blocks peripheral, but not central GABA receptors. All GABA effects were observed after oral and i.p. administration, but inhibition of gastric lesions was greater by the last route. Furthermore, GABA did not affect the acidity or the volume of gastric secretion in pylorus-ligated rats. Consequently its antiulcer activity appears to be mediated by factors unrelated to gastric acid secretion. Since the entry of GABA across blood-brain barrier is greatly restricted it may be concluded that stimulation of peripheral GABA receptors is primarily involved in its antiulcer action.