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217a Der einfluß von Morphin und Laevallorphan auf motilität, Sauerstoffverbrauch und Rektaltemperatur sowie den Gehalt des Gehirns der weißen maus an Kreatinphosphat, ATP, ADP, milchsäure, Glykogen und Coenzym
Abstracts 214 Effects of Cocaine on the Central Nervous System. J2. EI~ELBERG, H. LESSF. and F. P. GAULT (U.S.A.‘!.
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activity by atropine substitutes originates in the inhibition of a central cholinoceptive system. -__-._-_.-
.-.__
It has been found that cocaine, at a dose range of lo-20 mg/kg in cats, induces marked changes in the electrical activity recorded from the amygdaloid Combined Action of Morphine and complex. Depending on the dosage these changes 216 The Atropine. R. EEROLA (Finland). range from increax in the high voltage, 40 c/s, rhythmic pattern characteristic of this region, to There are greatly differing opinions in the convulsive discharges. These may be followed by literature concerning the combined action of morgeneralized seizures. Equivalent effective dosages phine and atropine given simultaneously. The in rats are larger by a factor of 3 to 4. In both earlier workers considered the joint action of these the concomitant behavioural changes species drugs antagonistic, later investigators reported that stronglv resemble those of “psychomotor epilepsy”. atropine enhanced the action of several central Studies on rats have shown that previous bilateral depressant drugs. The author’s own experiments amygdaloid destruction prevents the appearance of in white mice indicate that the combined action of Rats seizures after a convulsant dose of cocaine. morphine and atropine is synergistic, the type of are significantly protected against cocaine-induced synergism being additive. The criterion was lethal convulsions by chlorpromazme, rrserpine, dibentoxicity. The results will be presented matheamine and pyridoxine. Pretreatment with monomatically. amino-oxidaac inhibitors potentiates the convulsant actions of cocaine, while inhibition of catechol-O217aDer EinfluIJ ~0x1 Morphin nnd Laevallorphan methvltransferase does not. auf MotilitZit, Sauerstoffverbrauch und It is proposed that cocaine acts selectively on Rektaltemperatur sowie den Gehalt des brain structures employing an “adrenergic” type of Gehirns der weil3en Maw an Kreatintransmission. On the basis of these data it is also phosphat, ATP, ADP, Milchs&ure, Glykoproposed tbat scrotonin may be an important factor gen und Coenzym A. C:. J. ESTLER (Germany). in transmission in the amygdaloid complex.
215 Relationship
between Anti-Arecolin Activity and Potentiation of the Pseudo-narcotic Action of Morphine by Atropine Substitutes. :I. DERZ [German)-I.
Arccoline reduces the reaction to nociceptive stimulation in animals: this effect can be abolished by atropine-like substances possessing central activity. Quantitative proof of the anti-arecoline potency of atropine substitutes is obtained by employing Waffner’s method of testing anaelgesia in .Apart from this, centrally acting atropine mice.[” substitutes pntentiate themorphine-induced pseudonarcosis in the rat. A method has been developed to establish this potency quantitatively.‘” The activity of about 20 substances possessing more or less marked atropinc properties has been investigated in both tests; it was found that there exists a distinct correlation between the antiarecoline activity and the morphine-pseudonarcosis potentiating activity of the substances. hIost active is scopolamine; rt is followed in some distance by hyoscyamine and antiparkinsonian compounds, i.e. benactyzine, trihexyphenidyl, akineton, procyclidine, caramiphen and others; low activity or none at all was observed, for exampie, in substances like diphenllydramine and orphenachine and also in the dextro-rotary isomers of The effective optidally-active atropinr substitutes. doses of the investigated substances differ by nearly 10’. From these results it is suggested, that the potmtiation of the narcotic equivalents of morphine
An we&xl hIamen wurdr rine Stunde nach Verabreichung von hlorphin und Laevallorphan (3-Hydroxy-N-Allylmorphinan) cinzeln und in Kombination der FinfluB auf die Spontanmotilit~t. den Saucrstoffverbrauch, die Rektaltemperatur und den Grhalt tics Gehirns an Kreatinphosphat, ATP, XDP. Glykogen, hlilchsaure und Cocnxym A untcrsucht. Laevallorphan in einer Do&rung van 0.5, 1.0 und :7.0 mg/kg S.C. fuhrte zu keiner signifikanten .%nderung der untersuchtcn StoAivcchseigrijl3cn uncl dcr Motilitat. Fiinfzehn mg/kg Morphin S.C. riefen einr Steigerung der Spontanm&lit% auf clas 1%fache der Norm, sowie eine Senkung dcs Sauerstoffverbrauchs urn 12 Prozent und tine Ncrabsetzung drr Rrktaltemperatur urn 2.2 ,C: hervor. Im Gchirn sting miter nlorphin dct .4TP-Gehalt van 1.94 auf2.17 nhf/g? drr C&halt an :\DP sank urn annChernd den gleichen l%etrag ab, der Kreatinpllosphat-G~halt he1 van 3.24 auf 2.67 $vI/g. die Xlilchnaure van 1.49 auf 1. i 9 @i/g. Der Glykogcn- und Coenzym-A-Gehalt blieben unvcr%ndrrt. 1 ,O und in schwncherem hIa& 0.5 mg/kg I,aevallorphan wirkten gegentiber Morphin antagonistisch. So zeigten 1 Stundr nach gleichzeitiger Verabreichung von 15 mg/kg Morphin und 1 .O mg/kg Laevallorphan SaurrstofTverbrauch, Rektaltemperatur, ATP-, ADP- und Glykogcngehalt des Gehirns keine signifikanten Abv~eichungen von der Norm. Die Spon tanmotilitat war gering gesteigrrt, der Kreatinphosphatgehalt des Gehirns noch urn 0.30 @l/g verringert. Der durch Morphin herabgesetztc Xiilchs$uregehalt des Gehirns wurdr durch Laeval-
68
Abstracts of Papers
lorphan nicht beeinflul3t. Fiinf mg/kg Laevallorphan normalisierten die durch Morphin veranderte Sporltanmotilit~t, die RektaItemperatur und den Kreatinphosphatgeh~t des Gehirns. Der Sauerstoffverbrauch war signifikant gesenkt, desgleichen der ATP-, ADP- und Milchsluregehalt dcs Gehirns, der Glykogengehalt war erhoht. 2 l7b The Influence of Morphine and Laevallorphan on Motility, Oxygen Consumption and Rectal Temperature and on the GreatinePhosphate, ATP-, ADP-, Lactic Acid, Glycogen and Goenzyme-A Content of the Mouse Brain. C. J. ESTLER (Germany). The effect of morphine and Laevallorphan (3hydrory-N-allylmorphinan) when administered either separately or in combination on spontaneous motility, oxygen consumption, rectal temperature and the creatine-phosphate, ATP, ADP, glyco,gen, lactic acid and coenzyme-A content of brain was investigated 1 hour after they had been given to white mice. Laevallorphan in doses of 0.5, 1 .O and 5.0 mg/kg S.C. did not cause any significant changes in the metabolic processes tested or in motility. Fifteen mg/kg of se. morphine caused an increase of spontaneous motility to 18 times the normal as well as a decline in oxygen consumption by 12 per cent and a lowering of the rectal temperature by 2.2 ‘C. In the brain, morphine causrd a rise in the A’I’Plevel from 1.94 to 2.17 PM/~; the ADP-level fell approximately by the same amount; the creatinephosphate level fell from 3.24 to 2.67 lAM/g, the lactic acid level from 1.49 to I.19 @I/g. The glycogen and coenzyme-A content remained unLaevallorphan in doses of 1-O mg/kg or changed. to a lesser extent of 0.5 mg/kg had a morphineantagonistic effect. For example, 1 hour after the simultaneous administration of 15 mg/kg of morphine and of 1 *Omg/kg of Laevallorphan the oxygen consumption, rectal temperature, ATP-, ADP- and glycogen-levels of the brain showed no significant changes from the norm. Spontaneous motility was slightly increased, and the crea tine phosphate content of the brain was diminished by 0.30 PM/g. The lactic acid content of the brain which was diminished by morphine, was not affected by Laevallorphan. Five mgjkg of Laevallorphan counteracted the changes in spontaneous motility, rectal temperature and creatine-phosphate-content of the brain due to morphine. Oxygen-consumption was significantly diminished as well as the ATP-, ADP-, and lactic acid content of the brain; the giycogen content was raised. 218 Concerning the Analgesic and Antipyretic Activity of Some Anticoagulant Drugs and Vitamin K. V. KOVALC~K(Czechoslovakia). Siegmund et al. have described a new test on mice suitable for the investigation ofweak analgesics (causing painful irritation in the viscera). Their method was used to study the analgesic properties
of vitamin K, ethyl-biscoumacetate and phenylindandione derivatives. Although the analgesic properties of vitamin K arc widely recognized, it was only possible to confirm this using d’ArmourSmith’s method. In experiments where weak analgetics were found to be effective, none of the anticoagulants had any marked effects. However, analysing their effect on pyrexia it was found that some caused further increase of temperature, whereas vitamin K was practically ineffective. A critical analysis of the resuits was performed. 219 Analysis of the Central EEect of D-Tubocurarine Chloride in the Cat. H. KYMAGAI
(Japan). Cerebral electrical activities were recorded from six parts of the brain (caudate nucleus, amygdaloid nuclear complex, thalamic nucleus centre median, hippocampus, midbrain reticular formation, and cortex) of cats treated with gallamine triethiodide and kept under artificial respiration. About 30 min after microinjection of D-tubocurarine solution (0.006 ml of 3 mg/ml) into each of the subcortical nuclei, seizure discharges started in the hippocampus, then spread to other parts of the brain, Discharges were less marked when the cortex had partially been removed. Although similar seizure discharges were observed by topical application of the same drug to the cortex, the sequence of discharge spread was somewhat different from that after microinjection into other parts. The seizure discharges were not obtained by microinjection of analeptic agents which evoked seizure discharges when applied intravenously. 220 The Effect of Oral Antidiabetics on the Central Nervous System. A. K. PFEIFER, A. KALDOR, I?. UTORY and G. POC.&TSA(Hungary). In a previous paper it has been shown that Carbutamide (C) increases the toxicity and the narcosis potentiating effect ofethyl alcohol (Krildor, Pogatsa). As this effect is not correlated with hypoglycaemia, nor is the metabolism of ethyl alcohol influenced by C, a clirect effect of the drug on the central nervous system was assumed. In the present study it has been observed that C inhibits maximal electro-shock seizures in a dose of 100 mg/kg in rats, whereas Metrazol convulsions are unaffected. Spontaneous motility of mice whereas locomotor hyperremains unchanged, motility produced by Amphetamine decreases considerably. The compound decreasesAmphetamine toxicity, when the mice are kept in groups. When, however, each animal is kept separately, the toxicity remains unchanged. This observation should be emphasized, as tranquilizers exhibit similar characteristics, whereas hypnosedative drugs inhibit the toxicity in both circumstances. Just as with ethyl alcohol, thiopental narcosis is also potentiated significant1 The central effect of C is indicated by its analgesic characteristics, i.e.
of Papers
67
activity by atropine substitutes originates in the inhibition of a central cholinoceptive system. -__-._-_.-
.-.__
It has been found that cocaine, at a dose range of lo-20 mg/kg in cats, induces marked changes in the electrical activity recorded from the amygdaloid Combined Action of Morphine and complex. Depending on the dosage these changes 216 The Atropine. R. EEROLA (Finland). range from increax in the high voltage, 40 c/s, rhythmic pattern characteristic of this region, to There are greatly differing opinions in the convulsive discharges. These may be followed by literature concerning the combined action of morgeneralized seizures. Equivalent effective dosages phine and atropine given simultaneously. The in rats are larger by a factor of 3 to 4. In both earlier workers considered the joint action of these the concomitant behavioural changes species drugs antagonistic, later investigators reported that stronglv resemble those of “psychomotor epilepsy”. atropine enhanced the action of several central Studies on rats have shown that previous bilateral depressant drugs. The author’s own experiments amygdaloid destruction prevents the appearance of in white mice indicate that the combined action of Rats seizures after a convulsant dose of cocaine. morphine and atropine is synergistic, the type of are significantly protected against cocaine-induced synergism being additive. The criterion was lethal convulsions by chlorpromazme, rrserpine, dibentoxicity. The results will be presented matheamine and pyridoxine. Pretreatment with monomatically. amino-oxidaac inhibitors potentiates the convulsant actions of cocaine, while inhibition of catechol-O217aDer EinfluIJ ~0x1 Morphin nnd Laevallorphan methvltransferase does not. auf MotilitZit, Sauerstoffverbrauch und It is proposed that cocaine acts selectively on Rektaltemperatur sowie den Gehalt des brain structures employing an “adrenergic” type of Gehirns der weil3en Maw an Kreatintransmission. On the basis of these data it is also phosphat, ATP, ADP, Milchs&ure, Glykoproposed tbat scrotonin may be an important factor gen und Coenzym A. C:. J. ESTLER (Germany). in transmission in the amygdaloid complex.
215 Relationship
between Anti-Arecolin Activity and Potentiation of the Pseudo-narcotic Action of Morphine by Atropine Substitutes. :I. DERZ [German)-I.
Arccoline reduces the reaction to nociceptive stimulation in animals: this effect can be abolished by atropine-like substances possessing central activity. Quantitative proof of the anti-arecoline potency of atropine substitutes is obtained by employing Waffner’s method of testing anaelgesia in .Apart from this, centrally acting atropine mice.[” substitutes pntentiate themorphine-induced pseudonarcosis in the rat. A method has been developed to establish this potency quantitatively.‘” The activity of about 20 substances possessing more or less marked atropinc properties has been investigated in both tests; it was found that there exists a distinct correlation between the antiarecoline activity and the morphine-pseudonarcosis potentiating activity of the substances. hIost active is scopolamine; rt is followed in some distance by hyoscyamine and antiparkinsonian compounds, i.e. benactyzine, trihexyphenidyl, akineton, procyclidine, caramiphen and others; low activity or none at all was observed, for exampie, in substances like diphenllydramine and orphenachine and also in the dextro-rotary isomers of The effective optidally-active atropinr substitutes. doses of the investigated substances differ by nearly 10’. From these results it is suggested, that the potmtiation of the narcotic equivalents of morphine
An we&xl hIamen wurdr rine Stunde nach Verabreichung von hlorphin und Laevallorphan (3-Hydroxy-N-Allylmorphinan) cinzeln und in Kombination der FinfluB auf die Spontanmotilit~t. den Saucrstoffverbrauch, die Rektaltemperatur und den Grhalt tics Gehirns an Kreatinphosphat, ATP, XDP. Glykogen, hlilchsaure und Cocnxym A untcrsucht. Laevallorphan in einer Do&rung van 0.5, 1.0 und :7.0 mg/kg S.C. fuhrte zu keiner signifikanten .%nderung der untersuchtcn StoAivcchseigrijl3cn uncl dcr Motilitat. Fiinfzehn mg/kg Morphin S.C. riefen einr Steigerung der Spontanm&lit% auf clas 1%fache der Norm, sowie eine Senkung dcs Sauerstoffverbrauchs urn 12 Prozent und tine Ncrabsetzung drr Rrktaltemperatur urn 2.2 ,C: hervor. Im Gchirn sting miter nlorphin dct .4TP-Gehalt van 1.94 auf2.17 nhf/g? drr C&halt an :\DP sank urn annChernd den gleichen l%etrag ab, der Kreatinpllosphat-G~halt he1 van 3.24 auf 2.67 $vI/g. die Xlilchnaure van 1.49 auf 1. i 9 @i/g. Der Glykogcn- und Coenzym-A-Gehalt blieben unvcr%ndrrt. 1 ,O und in schwncherem hIa& 0.5 mg/kg I,aevallorphan wirkten gegentiber Morphin antagonistisch. So zeigten 1 Stundr nach gleichzeitiger Verabreichung von 15 mg/kg Morphin und 1 .O mg/kg Laevallorphan SaurrstofTverbrauch, Rektaltemperatur, ATP-, ADP- und Glykogcngehalt des Gehirns keine signifikanten Abv~eichungen von der Norm. Die Spon tanmotilitat war gering gesteigrrt, der Kreatinphosphatgehalt des Gehirns noch urn 0.30 @l/g verringert. Der durch Morphin herabgesetztc Xiilchs$uregehalt des Gehirns wurdr durch Laeval-
68
Abstracts of Papers
lorphan nicht beeinflul3t. Fiinf mg/kg Laevallorphan normalisierten die durch Morphin veranderte Sporltanmotilit~t, die RektaItemperatur und den Kreatinphosphatgeh~t des Gehirns. Der Sauerstoffverbrauch war signifikant gesenkt, desgleichen der ATP-, ADP- und Milchsluregehalt dcs Gehirns, der Glykogengehalt war erhoht. 2 l7b The Influence of Morphine and Laevallorphan on Motility, Oxygen Consumption and Rectal Temperature and on the GreatinePhosphate, ATP-, ADP-, Lactic Acid, Glycogen and Goenzyme-A Content of the Mouse Brain. C. J. ESTLER (Germany). The effect of morphine and Laevallorphan (3hydrory-N-allylmorphinan) when administered either separately or in combination on spontaneous motility, oxygen consumption, rectal temperature and the creatine-phosphate, ATP, ADP, glyco,gen, lactic acid and coenzyme-A content of brain was investigated 1 hour after they had been given to white mice. Laevallorphan in doses of 0.5, 1 .O and 5.0 mg/kg S.C. did not cause any significant changes in the metabolic processes tested or in motility. Fifteen mg/kg of se. morphine caused an increase of spontaneous motility to 18 times the normal as well as a decline in oxygen consumption by 12 per cent and a lowering of the rectal temperature by 2.2 ‘C. In the brain, morphine causrd a rise in the A’I’Plevel from 1.94 to 2.17 PM/~; the ADP-level fell approximately by the same amount; the creatinephosphate level fell from 3.24 to 2.67 lAM/g, the lactic acid level from 1.49 to I.19 @I/g. The glycogen and coenzyme-A content remained unLaevallorphan in doses of 1-O mg/kg or changed. to a lesser extent of 0.5 mg/kg had a morphineantagonistic effect. For example, 1 hour after the simultaneous administration of 15 mg/kg of morphine and of 1 *Omg/kg of Laevallorphan the oxygen consumption, rectal temperature, ATP-, ADP- and glycogen-levels of the brain showed no significant changes from the norm. Spontaneous motility was slightly increased, and the crea tine phosphate content of the brain was diminished by 0.30 PM/g. The lactic acid content of the brain which was diminished by morphine, was not affected by Laevallorphan. Five mgjkg of Laevallorphan counteracted the changes in spontaneous motility, rectal temperature and creatine-phosphate-content of the brain due to morphine. Oxygen-consumption was significantly diminished as well as the ATP-, ADP-, and lactic acid content of the brain; the giycogen content was raised. 218 Concerning the Analgesic and Antipyretic Activity of Some Anticoagulant Drugs and Vitamin K. V. KOVALC~K(Czechoslovakia). Siegmund et al. have described a new test on mice suitable for the investigation ofweak analgesics (causing painful irritation in the viscera). Their method was used to study the analgesic properties
of vitamin K, ethyl-biscoumacetate and phenylindandione derivatives. Although the analgesic properties of vitamin K arc widely recognized, it was only possible to confirm this using d’ArmourSmith’s method. In experiments where weak analgetics were found to be effective, none of the anticoagulants had any marked effects. However, analysing their effect on pyrexia it was found that some caused further increase of temperature, whereas vitamin K was practically ineffective. A critical analysis of the resuits was performed. 219 Analysis of the Central EEect of D-Tubocurarine Chloride in the Cat. H. KYMAGAI
(Japan). Cerebral electrical activities were recorded from six parts of the brain (caudate nucleus, amygdaloid nuclear complex, thalamic nucleus centre median, hippocampus, midbrain reticular formation, and cortex) of cats treated with gallamine triethiodide and kept under artificial respiration. About 30 min after microinjection of D-tubocurarine solution (0.006 ml of 3 mg/ml) into each of the subcortical nuclei, seizure discharges started in the hippocampus, then spread to other parts of the brain, Discharges were less marked when the cortex had partially been removed. Although similar seizure discharges were observed by topical application of the same drug to the cortex, the sequence of discharge spread was somewhat different from that after microinjection into other parts. The seizure discharges were not obtained by microinjection of analeptic agents which evoked seizure discharges when applied intravenously. 220 The Effect of Oral Antidiabetics on the Central Nervous System. A. K. PFEIFER, A. KALDOR, I?. UTORY and G. POC.&TSA(Hungary). In a previous paper it has been shown that Carbutamide (C) increases the toxicity and the narcosis potentiating effect ofethyl alcohol (Krildor, Pogatsa). As this effect is not correlated with hypoglycaemia, nor is the metabolism of ethyl alcohol influenced by C, a clirect effect of the drug on the central nervous system was assumed. In the present study it has been observed that C inhibits maximal electro-shock seizures in a dose of 100 mg/kg in rats, whereas Metrazol convulsions are unaffected. Spontaneous motility of mice whereas locomotor hyperremains unchanged, motility produced by Amphetamine decreases considerably. The compound decreasesAmphetamine toxicity, when the mice are kept in groups. When, however, each animal is kept separately, the toxicity remains unchanged. This observation should be emphasized, as tranquilizers exhibit similar characteristics, whereas hypnosedative drugs inhibit the toxicity in both circumstances. Just as with ethyl alcohol, thiopental narcosis is also potentiated significant1 The central effect of C is indicated by its analgesic characteristics, i.e.