Failure of (+)-naloxone to accelerate feline colonic transit

Summary To determine whether the colonic transit accelerating effect of (–)-naloxone (0.3 mg/kg, i.m.) is due to an action at opioid receptors or a direct pharmacologic effect, its enantiomer, (+)-naloxone (0.3 mg/kg, i.m.) was administered to cats and compared to saline control using colonic transit scintigraphy. Transit was not accelerated by (+)-naloxone. The effects of naloxone on colonic transit are thus stereospecific, and are probably mediated by opioid receptors.     

Blockade of GABAB receptors accelerates amygdala kindling development.

The aim of this study was to investigate the putative role of GABAB receptors in the development of amygdala kindling in rats. The effects of the GABAB blocker CGP 35348 and the GABAB agonist baclofen on the progressive development of behavioural seizure symptoms (stages 1-5 classified by Racine) and duration of after-discharges (AD) were studied. CGP 35348 at a dose of 300 mg/kg i.p., which blocks central GABAB receptors, moderately but consistently accelerated the development of behavioural seizure symptoms. CGP 35348 had no marked effect on the duration of ADs corresponding to the different seizure stages. L-baclofen (6 mg/kg i.p.) had a dual effect on kindling development. It retarded the development of the behavioural symptoms, but increased the duration of AD. In conclusion, the results suggest that synaptically-released GABA activated GABAB receptors and thereby exerted a depressant effect on kindling development.     

Blockade of GABAB receptors accelerates amygdala kindling development

The aim of this study was to investigate the putative role of GABA_B receptors in the development of amygdala kindling in rats. The effects of the GABA_B blocker CGP 35348 and the GABA_B agonist baclofen on the progressive development of behavioural seizure symptoms (stages 1–5 classified by Racine) and duration of afterdischarges (AD) were studied. CGP 35348 at a dose of 300 mg/kg i.p, which blocks central GABA_B receptors, moderately but consistently accelerated the development of behavioural seizure symptoms. CGP 35348 had no marked effect on the duration of ADs corresponding to the different seizure stages. L-baclofen (6 mg/kg i.p.) had a dual effect on kindling development. It retarded the development of the behavioural symptoms, but increased the duration of AD. In conclusion, the results suggest that synaptically-released GABA activated GABA_B receptors and thereby exerted a depressant effect on kindling development.     

Influence of flupirtine, a novel nonopioid analgesic agent on somatosensory evoked potentials in rats.

The effect of flupirtine, a novel nonopioid analgesic, on somatosensory evoked potentials (SEP) was investigated in anesthetized rats. Primary somatosensory potentials were evoked in the cerebral cortex by stimulation of the skin of the whiskery part of the face. Flupirtine injected i.p. dose-dependently prolonged the latency and reduced the amplitude of SEP with ID50-values of 5.4 mg/kg (2.6-9.3 mg/kg) and 7.9 mg/kg (3.9-13.8 mg/kg), respectively. This effect of flupirtine (10 mg/kg, i.p.) on the latency and the amplitude of SEP, did not change when naloxone (1 mg/kg, i.p.) was given before flupirtine. The results indicate that the analgesic flupirtine decreases the primary somatosensory evoked potential by diminishing the excitability of cortical neurons. Opioid mechanisms are not involved.     

Modification of the effect of cardio-accelerator nerve stimulation in dogs by clonidine and several alpha-adrenolytics]

In dogs anaesthetized with pentobarbital (30 mg. kg -1 i.v.), clonidine (0,01 mg.kg-1 i.v.) reduced the tachycardia induced at low frequencies by stimulation of the cardiac nerve. The effects of some alpha-adrenoceptor blocking agents on this effect have been studied. Small doses of yohimbine (0.3 mg. kg-1 i.v.) or piperoxan (0.3 mg. kg-1 i.v.) increased the effects of the stimulation and in addition antagonized the inhibitory effects of clonidine and reversed the pressor response to adrenaline. Thymoxamine (1 mg.kg-1 i.v.) and prazosin (1 mg.kg-1 i.v.) did not increase the effect of the stimulation of the cardiac nerve, but reduced the effect of clonidine. ARC239 (0.05 mg.kg-1) reversed the pressor response to adrenaline but even at high doses did not increase the effects of the stimulation of the cardiac nerve or the effects of clonidine. These observations afford further evidence for a dissimilarity between pre and post-synaptic alpha-adrenoceptors.     

The effects of physostigmine on the oxygen uptake in rat brain tissue

Summary Physostigmine in a dose of 0.1 mg/kg i.v. expressly stimulated the oxygen uptake in the rat cerebral cortex. This effect was blocked by propranolol and seems be mediated by catecholamines. Since atropine also antagonized the stimulant effect of physostigmine, it appears that the action of physostigmine is primarily cholinergic and that the adrenergic effect is a secondary phenomenon. The higher dose of physostigmine (0.4 mg/kg i.v.) caused a depression of rat brain oxygen uptake.This work was supported by a grant from Serbian Republic Scientific Fund (ZMNU SR Srbija), Belgrade (Yugoslavia).The authors wish to acknowledge the skilful technical assistance of Lj. Krsti.     

Influence of flupirtine,a novel nonopioid analgesic agent on somatosensory evoked potentials in rats

The effect of flupirtine, a novel nonopioid analgesic, on somatosensory evoked potentials (SEP) was investigated in anesthetized rats. Primary somatosensory potentials were evoked in the cerebral cortex by stimulation of the skin of the whiskery part of the face. Flupirtine injected i.p. dose-dependently prolonged the latency and reduced the amplitude of SEP with ID₅₀-values of 5.4 mg/kg (2.6–9.3 mg/kg) and 7.9 mg/kg (3.9–13.8 mg/kg), respectively. This effect of flupirtine (10 mg/kg, i.p.) on the latency and the amplitude of SEP, did not change when naloxone (1 mg/kg, i.p.) was given before flupirtine. The results indicate that the analgesic flupirtine decreases the primary somatosensory evoked potential by diminishing the excitability of cortical neurons. Opioid mechanisms are not involved.     

Effect of thiamine hydrochloride on the blood level of 2-formyl 1-methyl pyridinium oxime chloride (2-PAM.C1) in rats.

The biological half-life of 2-PAM.C1 was found to increase in female rats pretreated with thiamine hydrochloride (10 mg/kg i.m.). No such effect was observed in the male rats.     

Action of N-butylnorsympathone on the effects of cardioaccelerator nerve stimulation in the dog]

In Dogs anaesthetized with pentobarbital (30 mg . kg-1), N-butylnorsympathone (20 mg . kg-1 i.v.) reduced the bradycardia induced by stimulating the cardiac nerve (1, 2, 5, 10 Hz). Phentolamine (1 mg . kg-1 i.v.) or yohimbine (0.3 mg . kg-1 i.v.), two potent alpha-adrenoceptor blocking agents known to block presynaptic alpha-adrenoceptor induced a recovery of the effect of cardiac nerve stimulation. Prazosine (0.050 mg . kg-1 i.v.) an alpha-adrenoceptor blocking agent known to be ineffective on presynaptic alpha-adrenoceptors did not induce a recovery. However neither phentolamine or yohimbine were able to prevent the effects of N-butylnorsympathone. Neither haloperidol (0.050 to 2 mg . kg-1 i.v.) or pimozide (0.20 to 1 mg . kg-1 i.v.) induced a recovery or prevented the effects of N-butylnorsympathone. These results suggest that N-butylnorsympathone may stimulate presynaptic receptors which do not resemble classical presynaptic alpha-adrenoceptors or dopamine receptors.     

Naloxone prevents the analgesic action of alpha-MSH in mice

alpha-MSH (0.1, 1, 10 micrograms) was administered intracerebroventricularly and its action on pain sensitivity was investigated by the hot-plate method in mice. alpha-MSH produced dose-dependent analgesia and this analgesic effect was prevented by naloxone (1 mg/kg, s.c.). It is possible that alpha-MSH may play a role in the mechanism of pain through endogeneous opioid systems.     

Baclofen prevents rapid amygdala kindling in adult rats

This study investigates the effect of the gamma-aminobutyric acid (GABA_B) agonist, baclofen, on amygdala kindling in adult rats. Baclofen has been reported to be anticonvulsant in a variety of seizure models and prevents kindling in immature rats. These experiments describe the effects of baclofen (2, 5 and 10 mg/kg, i.p.) on the afterdischarge threshold and kindling rate. Baclofen, 10 mg/kg, significantly increased the afterdischarge threshold in the amygdala. Baclofen at 5 and 10 mg/kg, retarded the rate of kindling as measured by the number of stimuli required to advance to subsequent seizure stages. These results suggest that baclofen may decrease the local excitability of the amygdala and retard the rate of seizure spread (or generalization) throughout the brain. Baclofen, acting at GABA_B receptors exerts an anticonvulsant effect on amygdala kindling in these experiments.     

The effects of physostigmine on the oxygen uptake in rat brain tissue.

Physostigmine in a dose of 0.1 mg/kg i.v. expressly stimulated the oxygen uptake in the rat cerebral cortex. This effect was blocked by propranolol and seems be mediated by catecholamines. Since atropine also antagonized the stimulant effect of physostigmine, it appears that the action of physostigmine is primarily cholinergic and that the adrenergic effect is a secondary phenomenon. The higher dose of physostigmine (0.4 mg/kg i.v.) caused a depression of rat brain oxygen uptake.     

Prednisolon-Na-succinat und die Phagozytose der Leukozyten

Summary Intravenous administration of 3 mg/kg body weight prednisolon-Na-succinate (P) decreased, after 24 h, by 30% the bacterial phagocytosis of leukocytes of rabbits. After 48 h, the effect became a slight increase. At a dosis of 0.3 mg/kg, P exerts a stimulating effect which ceases within some hours. Inin vitro experiments, it showed increased or decreased action depending upon the concentration. When perfused through the liver, the efficacy of P rises strikingly.     

Absorption and biotransformation of L(+)-tartaric acid in rats

Summary Oral or parenteral doses of monosodium¹⁴C-L(+)-tartrate (400 mg/kg) are rapidly excreted by rats and a proportion completely metabolized to CO₂. The oral dose was well-absorbed.     

Effect of thiamine hydrochloride on the blood level of 2-formyl 1-methyl pyridinium oxime chloride (2-PAM.Cl) in rats

Summary The biological half-life of 2-PAM.Cl was found to increase in female rats pretreated with thiamine hydrochloride (10 mg/kg i.m.). No such effect was observed in the male rats.Dr B.L. Chowdhri very kindly synthesized the compound 2-PAM.Cl in the Department of Chemistry of this establishment for this work.The authors are thankful to Dr P.K. Ramachandran, Director, and Dr A.K. Chatterjee, Deputy Director, Defence Research and Development Establishment, Gwalior, for their keen interest in this work.     

The COMT inhibitor tolcapone potentiates the anticataleptic effect of Madopar in MPP+-lesioned mice

Orally administered Madopar (levodopa/benserazide 41) dose-dependently antagonized haloperidol-induced (1 mg/kg s.c.) catalepsy in MPP⁺-lesioned mice. Pretreatment with a new selective catechol-O-methyltransferase (COMT) inhibitor, tolcapone (30 mg/kg p.o.), slightly potentiated the antagonistic effect of Madopar (15 mg/kg p.o.) on haloperidol-induced catalepsy. The ability of tolcapone to increase the Madopar effect was significantly attenuated by high doses of 3-O-methyldopa (3-OMD) (800 mg/kg i.p.). This might suggest a competitive blockade of the active transport of levodopa through the blood-brain barrier. In conclusion, the inhibitory effect of tolcapone on the O-methylation of levodopa to 3-OMD by COMT is largely due to improved levodopa and dopamine availability in the brain, and to the reduced formation of 3-OMD.     

Acute toxicity and elimination of phenol injected into fish (Carassius auratus L.)

Riassunto Nel ciprino la DLM del fenolo è di 230 mg/kg i.m. Il fenolo, iniettato i.m. a dose di 200 mg/kg, viene eliminato in media per quasi il 90% nelle prime 4 ore come fenoli liberi. Sotto il profilo della tossicità, la mancata capacità a detossicare mediante coniugazione sembra nel pesce compensata dalla elevata capacità escretiva degli organi emuntori.     

Histamine-induced hypotension modified by H1 and H2 antagonists in the monkey (Macaca mulatta).

Blocking H2 receptors with burimamide in the dose used (20 mg/kg) approximately doubles the amount of histamine needed to produce the same effect as seen when H1 antagonists (chlorpheniramine or mepyramine) are used alone. The Kz ratios for chlorpheniramine-chlorpheniramine plus burimamide are 117-204 and for mepyramine-mepyramine phus burimamide are 200-478. H1 and H2 receptors, in the monkey, when stimulated, both cause cardiovascular responses in the same direction.     

Synergism between long-acting bromocryptine microcapsules and cyclosporine A in the prevention of various autoimmune diseases in rats

Pre-treatment of male Sprague-Dawley rats with long-acting bromocryptine microcapsules (CBLA) significantly inhibited the arthritic response to Freund's complete adjuvant and reduced weight loss, thymolysis, splenomegaly and leukocytosis. In the prevention of adjuvant arthritis (AA), the combination of CBLA plus sub-optimal doses of cyclosporine A (CsA) was more efficient than either of the drugs alone. Sub-optimal doses of CsA were 0.1 and 1.0 mg/kg/day s.c. for 5 days. Furthermore, CBLA alone did not decrease the incidence of experimental allergic uveitis (EAU) in the male Lewis rats. Low-dose CsA reduced the incidence of uveitis by 50%, and with the addition of CBLA, 100% of rats were protected. Low-dose CsA was 2 mg/kg/day i.m. for 14 days. Long-term treatment of male Sprague-Dawley rats with CBLA alone reduced the incidence and severity of spontaneous autoimmune periateritis nodosa (PN) in a dose-dependent manner; CsA was less potent than CBLA, and only additive effects were obtained. Finally, for the prevention of spontaneous autoimmune insulin-dependent diabetes (DM), the administration of CBLA did not improve the effect of a low-dose CsA in male BB rats. Nevertheless, a delay in onset of DM could be achieved. A sequential therapy using CsA plus CBLA clearly showed beneficial effects. The dose of CsA was 10 mg/kg p.o. 6 days/week for 21 weeks. Compared with Sprague-Dawley or Lewis male rats, BB male rats showed only weak prolactin suppression after the same doses of CBLA. It is suggested that the use of CBLA may be particularly beneficial in autoimmune disorders. The effectiveness of the combination therapy CBLA plus CsA, however, was dependent on the model considered. Various factors could play a role: (1) the different ways of administering CsA (s.c. in AA, i.m. in EAU and PN, oral in DM); (2) strain-dependency in the capacity of CBLA to suppress Prl secretion; and(3) at least in the BB rats, the transient increase of CsA bioavailibility which was possibly induced by CBLA.     

Dämpfung des Kältezitterns durch Pentobarbital und Pethidin bei Ratten

Summary In rats, shivering was induced by cooling. Shivering started at 36.6°C in unanaesthetized rats and at 36.0°C in animals with light pentobarbital anaesthesia (5 mg/kg i.V.). Pethidine (2 mg/kg) lowered the onset of shivering in unanaesthetized rats to 35.3 °C and in anaesthetized animals to 33.0°C. The results suggest that the effect of pethidine upon shivering is potentiated by pentobarbital.