bluuebunny/crossref_metadata_2025_split huggingface dataset:
Determination of receptors that mediate opiate side effects in the mouse
Authors: Hayes Ann. G. , Tyers MichaelB. 
Published: July 2012

The effects of μ and κ‐opiate receptor agonists were studied in a variety of tests in the mouse designed to correspond to clinical side‐effects in man. These included sedation, decrease in pupil diameter, Straub tail, decrease in body temperature, decrease in respiratory rate and inhibition of gut propulsion.
The μ‐receptor agonists tested produced opiate side‐effects in the mouse at doses between 2.4 and 34 times higher than their antinociceptive doses in the abdominal constriction test. Their ranked orders of potency in producing these effects were very similar to their order of antinociceptive potency.
In contrast, the κ‐receptor agonists only produced opiate side‐effects at doses between 29 and >2500 times higher than their antinociceptive doses. There was no correlation between the potency ratios in these tests and in the abdominal constriction test.
It is concluded that μ‐receptor agonists may produce both their antinociceptive effects and opiate side‐effects by interacting with the μ‐receptor. The κ‐receptor agonists have previously been shown to produce antinociception via the κ‐receptor, but the opiate‐like side‐effects which appear with some of the drugs at much higher doses are probably due either to interaction with the μ‐receptor or to some other non‐specific action.
Vascular reactivity in diabetes mellitus: role of the endothelial cell
Authors: Fortes Zuleica B. , Lerne J. Garcia , Scivoletto Regina 
Published: July 2012

The response to vasoactive agents of microvessels in situ and large arteries in vitro was compared in normal and alloxan‐diabetic rats.
Noradrenaline was equally effective in evoking a constrictor response of mesenteric microvessels in normal and diabetic animals.
The constrictor response to a standard amount of noradrenaline in such vessels was fully antagonized by acetylcholine or papaverine, the minimum effective doses being equivalent in normal and diabetic animals. In contrast, the minimum doses of histamine or bradykinin, effective in normal animals, had to be increased about 20 fold to be active in diabetic animals.
Increased osmolarity of extracellular fluid caused a significant and equivalent increase in latency of the vasoconstrictor response of microvessels to noradrenaline in normal and diabetic animals.
Concentration‐effect curves, constructed from the response of isolated aortae to noradrenaline, were similar in normal and diabetic animals, provided the endothelium was removed. Diabetes only affected preparations in which the endothelium was left intact. In these, the median effective concentrations of noradrenaline were greatly increased in comparison with normal values.
Precontracted aortae from normal and diabetic animals were equally relaxed by acetylcholine and histamine, provided the endothelium was left intact. Loss of the relaxant response of the preparations in all groups of animals was observed following removal of endothelial cells.
It is suggested that different mechanisms may be involved in the effects of vasodilator agents on large arteries in vitro or small vessels in situ. Histamine and bradykinin which are potent permeability‐increasing factors, may antagonize the vasoconstrictor response of microvessels to noradrenaline through an action on endothelial cells with increased vascular permeability and temporary changes in composition of extracellular fluid. The reactive process of endothelial cells to permeability factors was affected by diabetes mellitus. However, the response of microvessels to acetylcholine and papaverine which are devoid of permeability‐increasing properties, was not influenced by diabetes.
Antinociceptive properties of thyrotropin releasing hormone in mice: comparison with morphine
Authors: Boschi Gabrielle , Desiles Marguerite , Reny Veronique , Rips Richard , Wrigglesworth Susan 
Published: July 2012

To investigate the antinociceptive activity of thyrotropin releasing hormone (TRH) in mice, different nociceptive stimuli were used. TRH (i.p.) was active in the phenyl‐p‐benzoquinone or acetic acid‐induced writhing tests (chemical stimuli) and in Haffner's test (mechanical stimulus); its action decreased rapidly 15 min after intraperitoneal injection.
To determine whether the activity of TRH has a peripheral or central origin, we administered TRH intracerebroventricularly via cannulae previously implanted in mice. The results provide evidence that a central mechanism is involved in the analgesic effect of TRH since when given intracerebroventricularly it was 10,000 and 1,000 times more active against chemical and mechanical stimuli respectively than intraperitoneally. The action of TRH decreased rapidly 5 min after i.c.v. injection. Morphine was studied in these tests and it was found that at the peak effect TRH analgesia (i.c.v.) was greater than that of morphine (i.c.v.) on a molar basis.
To investigate the mechanisms involved in the antinociceptive action of TRH, the effects of pre treatment with either agonists or antagonists of noradrenaline (NA), dopamine and 5‐hydroxytryptamine (5‐HT), or with naloxone were studied. TRH activity was generally resistant to modifications of NA, dopamine and 5‐HT systems. The TRH effect was not antagonized by naloxone, but TRH at a non‐analgesic dose prevented the hyperalgesia induced by naloxone.
In conclusion, TRH i.c.v. possessed a short, strong antinociceptive activity against chemical and mechanical stimuli. This analgesia was at least equipotent to that of morphine i.c.v.
Studies on the antinociceptive action of α‐agonist drugs and their interactions with opioid mechanisms
Authors: Bentley G.A. , Newton S.H. , Starr Jennifer 
Published: July 2012

A modified abdominal constriction test, whereby the drugs used are injected intraperitoneally when the writhing response is maximal, has been used to study the antinociceptive activity of various sympathomimetic drugs. Of those tested, clonidine was the most potent, with an ID50 value in the nanomolar range. (—)‐Isoprenaline, (—)‐adrenaline and (—)‐noradrenaline were only a little less potent. Phenylephrine, the least potent, had only about one‐sixtieth of the activity of clonidine.
The antinociceptive action appears to occur within the peritoneum, since it was apparent almost immediately after the drugs were injected and was produced by doses far smaller than were effective by the subcutaneous route.
α‐Adrenoceptors appear to be involved in the reaction, since noradrenaline showed stereos‐pecificity, and the α‐adrenoceptor antagonists phentolamine and piperoxan both shifted the dose‐response curves of the α‐adrenoceptor agonist drugs to the right, usually parallel to the control curves.
The high antinociceptive potency of clonidine and oxymetazoline, indicate the importance of α2‐adrenoceptors and this was supported by the finding that piperoxan was a more effective antagonist than phentolamine. The moderate potency of phenylephrine suggests that α1‐adrenoceptors may also be involved, although the selective α1‐antagonist, prazosin, did not antagonize noradrenaline and had antinociceptive activity of its own.
β‐Adrenoceptors also appear to be involved in the antinociceptive response, since propranalol antagonized the effect of isoprenaline, but not that of clonidine.
Piperoxan was a very effective antagonist of morphine, while phentolamine had a weaker action. Naloxone had little action against the α‐adrenoceptor agonists.
Mice pretreated with clonidine or oxymetazoline but not noradrenaline showed a very great cross‐tolerance to morphine. Morphine pretreatment caused marked desensitization of itself, but little cross‐tolerance to clonidine or oxymetazoline.
It is suggested that sensory nerves in the mouse peritoneum have α2‐ and β‐adrenoceptors on their terminals, and possibly α1‐receptors also. It is possible that when activated by the appropriate agonists they depress the generation of pain impulses. There is an interaction between the α‐adrenoceptors and opioid receptors in the mouse peritoneum.
Electrophysiological effects of imipramine in non‐treated and in imipramine‐pretreated rat atrial fibres
Authors: Manzanares J. , Tamargo J. 
Published: July 2012

The effect of imipramine (Imip) in concentrations between 10−7M and 5 × 10−5M has been studied on rat atrial transmembrane potentials. In another group of experiments the effect of Imip was studied in atrial fibres from rats pretreated for 24 days with twice daily intraperitoneal injections of Imip 7.5 mg/kg or saline.
In non‐treated atria Imip depressed action potential amplitude and Vmax, reduced the resting membrane potential and shifted the membrane responsiveness and recovery time curves downward and to the right.
Imip also prolonged the action potential duration and the effective refractory period, lengthening the effective refractory period relative to action potential duration.
Pretreatment with Imip decreased the resting membrane potential, amplitude and Vmax of the action potential and prolonged the effective refractory period. Further addition of Imip produced similar but more marked changes than in non‐treated animals.
Imip suppressed the spontaneous atrial automaticity as well as the abnormal automaticity induced by BaCl2, aconitine, ouabain or isoprenaline.
The drug produced a negative inotropic effect and depressed the amplitude of the slow contractions elicited by isoprenaline in K‐depolarized atria.
It is concluded that even when the effects of Imip are similar to those of quinidine (group I of antiarrythmics), it also produces a reduction in Ca and K conductances.
The antinociceptive activity of meptazinol depends on both opiate and cholinergic mechanisms
Authors: Bill D.J. , Hartley J.E. , Stephens R.J. , Thompson A.M. 
Published: July 2012

Antinociceptive responses to meptazinol, morphine and oxotremorine and the effects of pretreatment with naloxone or scopolamine on these responses in mice and rats, were examined.
Meptazinol evoked larger increases in nociceptive thresholds in the mouse than in the rat, whereas morphine induced large increases in both species. Oxotremorine was both a more potent and a more effective antinociceptive agent in the mouse than in the rat.
Antinociceptive responses to meptazinol were consistently inhibited in animals pretreated with naloxone, whereas scopolamine attenuated the effects of meptazinol in some, particularly the mouse tail immersion test, but not in all of the procedures used.
Naloxone inhibited all antinociceptive responses to morphine, and scopolamine inhibited all responses to oxotremorine. However, there was no significant interaction between naloxone and oxotremorine or between scopolamine and various opioid analgesic agents.
These results indicate that meptazinol, unlike established opioid drugs, may induce antinociception by a dual action on opiate and cholinergic mechanisms.
Membrane potential responses to ionophoretically applied α‐adrenoceptor agonists in the mouse anococcygeus muscle
Authors: Large W. A. 
Published: July 2012

Noradrenaline, phenylephrine, naphazoline and oxymetazoline were applied by ionophoresis to the mouse anococcygeus muscle and the membrane potential was recorded with an intracellular microelectrode.
The ionophoretic application of noradrenaline and phenylephrine produced dose‐related depolarizations in 96% of the cells tested; in contrast, naphazoline and oxymetazoline depolarized only 62% of the cells although contraction was always seen.
The depolarizations produced by all four drugs had similar characteristics in shape and time course except that the latency of responses induced by the imidazoline‐related drugs was significantly longer than the value obtained with the phenylethanolamines. This discrepancy was not due to the difference in susceptibility to neuronal uptake of the two groups of drugs.
The time to peak depolarization for naphazoline and oxymetazoline was longer than that for noradrenaline and phenylephrine but was not sufficient to account for the considerably slower contraction produced by the former drugs.
At room temperature the sensitivity of the mouse anococcygeus to ionophoretically applied naphazoline and oxymetazoline was significantly lower than that to noradrenaline and phenylephrine but at 35°C the sensitivity was similar for all drugs.
These results suggest that there might be two subclasses of α1‐adrenoceptor in the mouse anococcygeus; stimulation of one type leads to depolarization and contraction and activation of the other class produces contraction with no change in membrane potential.
Effects of pancuronium and hexamethonium on paraoxon‐induced twitch potentiation and antidromic firing in rat phrenic nerve diaphragm preparations
Authors: Clark Amanda L. , Hobbiger F. , Terrar D.A. 
Published: July 2012

The actions of pancuronium, a selective antagonist of acetylcholine (ACh) at nicotinic cholinoceptors at motor endplates, and hexamethonium, a selective antagonist of ACh at nicotinic cholinoceptors in autonomic ganglia, have been studied in rat phrenic nerve diaphragm preparations. The effects on paraoxon‐induced twitch potentiation and antidromic firing (ADF) in the phrenic nerve, were compared with the effects on normal twitch tension and intracellularly recorded miniature endplate potentials (m.e.p.ps) and endplate potentials (e.p.ps.)
In preparations exposed to paraoxon, pancuronium was found to be approximately 10 times more effective in reducing the potentiated component of the twitch than the component which corresponded to the pre‐paraoxon twitch. A similar result was obtained with hexamethonium.
Pancuronium and hexamethonium, in concentrations which reduced paraoxon‐induced twitch potentiation but had no effect on the twitch tension of preparations not treated with paraoxon, reduced paraoxon‐induced ADF. The lowest concentrations of pancuronium and hexamethonium required for this also reduced the amplitude of m.e.p.ps and e.p.ps.
Dithiothreitol, a disulphide bond reducing agent which reduces the affinity of ACh for nicotinic cholinoceptors, enhanced the potency of pancuronium 2 to 3 fold. The same also applied for hexamethonium.
It is concluded that the experiments failed to provide evidence for an action of ACh on prejunctional nicotinic cholinoceptors of the ganglionic‐type being involved in the initiation by paraoxon of twitch potentiation and ADF. Furthermore, the results obtained can be explained by pancuronium and hexamethonium reducing the action of ACh at the postjunctional membrane.
Effects of apamin on α‐adrenoceptor‐mediated changes in plasma potassium in guinea‐pigs
Authors: Coats Rachel A. 
Published: July 2012

An intravenous K+‐sensitive electrode has been used to monitor plasma [K+] changes induced by adrenaline (1.4–6.8 μg kg−1) and amidephrine (14–340 μg kg−1) in anaesthetized guinea‐pigs.
A biphasic response consisting of an initial increase in [K+] followed, within 1 min, by a fall below baseline was observed with both agonists.
Apamin (0.4–40 μg kg−1) reduced the hyperkalaemic phase of the response to amidephrine in a dose‐related, non‐competitive manner. The response to adrenaline was also reduced but to a lesser extent.
Apamin caused little or no reduction of the hypokalemic phase of the response to either agonist.
Effects of various antipsychotic drugs upon the striatal concentrations of para‐hydroxyphenylacetic acid and meta‐hydroxyphenylacetic acid in the mouse
Authors: Juorio A.V. , McQuade P.S. 
Published: July 2012

The endogenous concentrations of p‐ and m‐hydroxyphenylacetic acid in the mouse caudate nucleus were determined by a gas chromatographic or a gas chromatographic‐mass spectrometry technique and the concentrations were about 30 and 11 ng g−1 respectively.
The subcutaneous administration of (+)‐butaclamol (1 mg kg−1), haloperidol (5 mg kg−1), molindone (100 mg kg−1), sulpiride (50 mg kg−1) or chlorpromazine (20 mg kg−1) increased the concentration of mouse striatal p‐ and m‐hydroxyphenylacetic acid; the effects were observed at 2 h after drug administration.
Lower doses of chlorpromazine (2 mg kg−1), haloperidol (0.2 mg kg−1) and molindone (2 mg kg−1) did not affect p‐ or m‐hydroxyphenylacetic acid concentrations.
The time course for the concentration changes produced by chlorpromazine (20 mg kg−1) revealed that the formation of the metabolites occurred within 30 min after its administration and that their efflux from the caudate nucleus took at least 4 h for p‐hydroxyphenylacetic acid and more than 8 h for m‐hydroxyphenylacetic acid.
Promethazine and (‐)‐butaclamol which have chemical structures related to chlorpromazine or (+)‐butaclamol respectively but which lack antipsychotic activity, produced no effect on striatal p‐ or m‐hydroxyphenylacetic acid concentrations.
The results suggest that antipsychotic drugs increase the utilization of mouse striatal p‐ and m‐tyramine and that after use the amines are metabolized by monoamine oxidase to form p‐ or m‐hydroxyphenylacetic acid. The synthesis of the acid metabolites occurs within 30 min after chlorpromazine administration and their efflux from the caudate nucleus takes from 4–8 h.
Characterization of the locomotor stimulant action of nicotine in tolerant rats
Authors: Clarke P.B.S. , Kumar R. 
Published: July 2012

Tests of locomotor activity (photocell cages) were used to investigate the development of tolerance to nicotine in rats. Repeated exposure to the apparatus did not influence the rate at which tolerance was acquired.
Comparisons of (+)‐nicotine (0.4–1.6 mg kg−1, s.c.) and (‐)‐nicotine (0.1–0.4 mg kg−1, s.c.) in tolerant rats showed that the (‐)‐isomer Was at least ten times more potent in stimulating motor activity.
Subcutaneous pretreatment with mecamylamine (1.0 mg kg−1) completely prevented the locomotor stimulant action of nicotine in tolerant rats, whereas chlorisondamine (0.01 or 0.1 mg kg−1 s.c.) only partially reduced it. When mecamylamine was given after an injection of nicotine, the locomotor stimulant action of nicotine was blocked, and nicotine actually reduced activity.
A single intraventricular dose of chlorisondamine (2 μg) blocked the stimulant actions of nicotine for the duration of the experiment (23–24 days).
Haemodynamic factors influencing myocardial ischaemia in a canine model of coronary artery stenosis: the effects of nitroglycerine
Authors: Szekeres L. , Udvary Éva 
Published: July 2012

At a critical degree of coronary stenosis (allowing a just adequate blood supply to the poststenotic area only at the expense of maximal hypoxic coronary vasodilatation), an additional loading of the heart induced marked local myocardial ischaemia, as indicated by appropriate biochemical, electrophysiological and haemodynamic changes.
In this model myocardial oxygen demand was increased in three different ways: (i) increasing heart rate by atrial pacing; (ii) increasing afterload by aortic occlusion and (iii) increasing preload by blood infusion. These procedures were compared in their ability to produce local myocardial ischaemia and characterized by ST‐segment elevation recorded from the endocardium and epicardium.
Increasing afterload evoked the mildest degree of ischaemia since the resulting increase in coronary perfusion pressure and coronary flow almost met the augmented myocardial oxygen demand evoked by the elevated peripheral resistance and by the simultaneously increased preload. A rather more pronounced ischaemia was produced by increasing the preload. The most serious ischaemia of all was induced by atrial pacing. This reduced coronary flow and perfusion pressure and increased left ventricular end diastolic pressure (LVEDP).
Nitroglycerine transiently reduced blood pressure and coronary blood flow and increased epicardial and endocardial ST‐segment elevation; the changes had disappeared 10 min after terminating the infusion. However, at this time a prolonged protective action against pacing‐induced ST‐segment elevation was observed. This protection was also seen after intracoronary injections of nitroglycerine. This indicated that part of the beneficial effect of nitroglycerine in ischaemia is due to direct coronary and/or myocardial actions.
The effects of calcium channel inhibitors and other procedures affecting calcium translocation on drug‐induced rhythmic contractions in the rat vas deferens
Authors: Hay D.W.P. , Wadsworth R.M. 
Published: July 2012

In the rat isolated vas deferens, methoxamine 8.1 μm produced an initial phasic response that declined towards baseline and was followed by rhythmic contractions that continued until wash‐out. These responses were predominant in the epididymal half. BaCl2 1 mm produced a similar type of response which was not mediated by noradrenaline release or activation of α‐adrenoceptors. The barium responses were similar in the epididymal and prostatic halves.
Incubation in nominally Ca2+‐free solution caused abolition or near abolition of rhythmic contractions produced by barium or methoxamine. The initial phasic response to methoxamine was abolished in Ca2+‐free solution, whereas that produced by barium persisted.
Rhythmic contractions produced by methoxamine or barium were inhibited by Mg2+ (2.4–20 mm) and by La3+ (1–5 mm). Mg2+ had selectivity for inhibition of the frequency of methoxamine‐ but not barium‐induced rhythmic contractions.
Despite their dependence on [Ca2+]o, barium‐ and methoxamine‐induced rhythmic contractions were resistant to inhibition by calcium channel inhibitors. Verapamil, nifedipine and flunarazine inhibited the amplitude of rhythmic contractions more readily than the frequency (methoxamine IC50 for verapamil: amplitude = 29.8 ± 5.40 μm, n = 6, frequency = 96.7 ± 31.0 μm, n = 5, for nifedipine: amplitude = 2.42 ± 0.34 μm, n = 7, frequency = 3.24 ± 0.75 μm, n = 7, and for flunarizine: amplitude = 15.9 ± 5.95 μm, n = 7, frequency = 153 ± 28.6 μm, n = 7). There was no differentiation between inhibition of methoxamine and barium‐induced responses.
Like Mg2+, methoxyverapamil selectively inhibited the frequency of methoxamine‐induced contractions (IC50: amplitude = 16.8 ± 2.86 μm, n = 5, frequency = 2.07 ± 0.81 μm, n = 5) but not barium‐induced contractions (IC50: amplitude = 13.9 ± 1.95 μm, n = 5, frequency = 48.5 ± 8.98 μm, n = 5).
Diazoxide (43.3–2167 μm) and nitroprusside (3.36–6712 μm) had only a small effect on barium contractions, but produced a dose‐related reduction in the amplitude of methoxamine‐induced responses. Diazoxide and nitroprusside caused methoxamine contractions to occur in groups, although they had no effect on their overall frequency.
It is concluded that barium‐ and methoxamine‐induced rhythmic contractions in the rat vas deferens are mediated by the entry of [Ca2+]o via membrane calcium channels that have a lower affinity (10–100 ×) for calcium channel inhibitors than those mediating the KCl response. Channels activated by methoxamine are concentrated in the epididymal half, whereas those opened by barium are evenly distributed. However, although responses to methoxamine and barium are similar in form, differences in the effects of some of the drugs tested, together with the results of previous studies, indicate that they produce contractions by different mechanisms.
The myotoxicity of bupivacaine, a 31P n.m.r. investigation
Authors: Newman Raymond J. , Radda George K. 
Published: July 2012

Phosphorus nuclear magnetic resonance (n.m.r.) spectroscopy is a recently introduced method for the non‐invasive study of muscle biochemistry.
It was shown in the rat that an intramuscular injection of the drug resulted in degeneration that was reflected spectroscopically in a progressive decrease in the intracellular concentrations of phosphocreatine and adenosine triphosphate without a corresponding rise in that of inorganic phosphate. Furthermore, ATP was depleted in the presence of significant levels of phosphocreatine. As regeneration occurred spectra returned to normal and this was complete by day 10.
No such spectroscopic effects were demonstrated in man following the use of bupivacaine in an intravenous regional anaesthetic.
It is suggested that further studies in man are required before this drug can be administered intramuscularly with confidence.