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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 50 (1972), S. 401-409 
    ISSN: 1432-1440
    Keywords: Opioids ; central nervous system ; neurotransmitters ; Opioide ; Zentralnervensystem ; Neurotransmitter
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Es wird eine Übersicht über die wichtigsten bekannten Stoffwechselveränderungen im Gehirn unter Einfluß von morphinartig wirkenden Substanzen („Opioiden“) gegeben. Von besonderem Interesse sind die mutmaßlichen zentralen Überträgersubstanzen, vor allem Katecholamine und Serotonin. Eine Wechselwirkung der Opioide mit diesen beiden Systemen ist sicherlich wichtig für das Zustandekommen bekannter zentraler Opioidwirkungen (z. B. Analgesie), während die Rolle des zentralen Acetylcholins noch ungeklärt ist, obwohl Opioide auch in den Stoffwechsel dieser Substanz eingreifen. Die Struktur-Wirkungs-Beziehungen von Opioiden werden kurz skizziert. Die Mechanismen, die bei der Entwicklung einer Gewöhnung und einer somatisch nachweisbaren (physischen) Abhängigkeit beteiligt sind, sind noch weitgehend unbekannt. Es gibt Hinweise darauf, daß die Induktion eines oder mehrerer, noch unbekannter Enzyme hierfür von Bedeutung ist. Auch hier spielen vermutlich Katecholamine und Serotonin eine Rolle. Schließlich wird auf die klinische Bedeutung dieser zentralen Wirkungsmechanismen im Hinblick auf mögliche Wechselwirkungen mit anderen, zentral wirksamen Pharmaka eingegangen.
    Notes: Summary A review is presented on the most important changes observed in the brain under the influence of narcotic analgesic drugs (“opioids”). The putative central neurotransmitters, particularly catecholamines and serotonin, are of special interest. An interaction of narcotic analgesics with both transmitter systems is probably relevant for the development of well-known central effects (e.g. analgesia). The role of central acetylcholine is still unknown, although the metabolism of this transmitter is influenced by narcotic analgesics, too. Then the structure-activity relationship of “opioids” is briefly discussed. The knowledge of mechanisms involved in the development of tolerance and physical dependence is rather poor. Induction of one or several enzymes, which are still unknown, might be of interest with regard to these phenomena; and catecholamines and serotonin are probably also involved in this. Finally, the clinical relevance of these central mechanisms is discussed with regard to possible interactions with other, centrally active drugs.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 57 (1979), S. 701-710 
    ISSN: 1432-1440
    Keywords: Endorphins ; Enkephalins ; Opioid Receptors ; Endorphine ; Enkephaline ; Opioid-Rezeptoren
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Die vor wenigen Jahren entdeckten Endorphine sind Peptide mit Opioid-ähnlicher Wirkung, die in verschiedenen Geweben des Organismus, vor allem im Darm und im Zentralnervensystem, synthetisiert werden. Die Entdeckung dieser Substanzgruppe war erst möglich, nachdem Opioid-spezifische Rezeptoren exakt charakterisiert werden konnten und sehr empfindliche Testmethoden für Opioide entwickelt worden waren. Die beiden zuerst entdeckten Endorphine, die Enkephaline, sind Pentapeptide, von denen das met-Enkephalin (H-Tyr-Gly-Gly-Phe-Met-OH) offenbar ein Bruchstück der ebenfalls Opioid-ähnliche Wirkung zeigenden Peptide α- und β-Endorphin sowie des in dieser Hinsicht unwirksamen Polypeptids β-Lipotropin ist: Alle diese Peptide enthalten die Sequenz von met-Enkephalin. β-Lipotropin und ACTH entstammen sehr wahrscheinlich einer gemeinsamen Vorstufe. Mindestens die (besonders gut untersuchten) Enkephaline entstehen offensichtlich im Zellkörper und werden von dort zur Nervenendigung transportiert, wo sie freigesetzt werden und vermutlich als Neuromodulatoren oder sogar Neurotransmitter fungieren. Endorphine zeigen ein ähnliches pharmakologisches Wirkungsspektrum wie “klassische Opiate”, z.B. eine analgetische Wirkung. Endorphine, oder genauer gesagt, die Enkephaline, sind unter anderem an verschiedenen, für die Schmerzperzeption und-transmission „strategisch“ wichtigen Stellen des Zentralnervensystems lokalisiert. Vermutlich spielen sie unter gewissen Bedingungen bei der Regulation der Schmerzperzeption eine Rolle. Eine weitere Bedeutung dieser Substanzen scheint in der Regulation verschiedener neuroendokriner Prozesse zu liegen. Fraglicher ist ihre Signifikanz beim Zustandekommen bestimmter Symptome schizophrener Psychosen. Im Zustand der Opiat-Abhängigkeit konnten bisher keine nennenswerten Veränderungen des Enkephalin-Gehaltes festgestellt werden.
    Notes: Summary Endorphins are peptides with opiate-like action synthesized in various tissues, e.g. in intestine and central nervous system. Exact characterization of opioid-specific receptors and sensitive biological test assays for opioids were prerequisites for the discovery of these substances. Met- and leu-enkephalin were the first endorphins discovered. Both are pentapeptides. One of them, namely met-enkephalin (H-Tyr-Gly-Gly-Phe-Met-OH) is likely to be a fragment of the peptides α- and β-endorphin, both showing opioid-like actions, as well as of β-lipotropin, a polypeptide showing no opioid-like activity: all these peptides include the pentapeptide met-enkephalin within their molecules. β-lipotropin and ACTH are likely to be fragments of a common precursor. At least both enkephalins (which are studied better as yet than the other endorphins) are supposed to be formed in the soma of the neuron and transported to the nerve ending, where they are released. They seem to have the function of neuromodulators or even of neurotransmitters. The pharmacological actions of endorphins resemble those of “classical opiates”, both having e.g. analgesic effects. Both enkephalins are, among various other brain and spinal cord areas, localized in those areas which seem to be of particular relevance for perception and transmission of pain. They might, under certain conditions, play some part in the regulation of pain perception. Furthermore, they seem to be relevant for some neuroendocrine processes. Their relevance in symptoms of schizophrenic psychoses seems to be more doubtful. In opiate dependence no significant alterations of endorphin concentrations could be observed as yet.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The hydroxyl radical is a very reactive oxygen species that damages biomolecules in the brain and in other tissues. The possible pharmacological intervention to prevent hydroxyl radical formation was studied in vivo using the microdialysis technique in brains of nonanesthetized rats. Hydroxyl radicals form stable adducts [mainly 2,3-dihydroxybenzoic acid (2,3-DHBA) and 2,5-DHBA)] via an aromatic hydroxylation reaction with salicylic acid. 2,3-DHBA was separated and quantified by HPLC and electrochemical detection. Microdialysis probes were implanted into the striatum 1 day before measurement of levels of hydroxyl radicals. The next day, the probes were first perfused for 120 min with a modified Ringer's solution containing 5 mM salicylic acid, to obtain stable baselines. Afterward, the perfusion solution was switched to another solution that in addition contained 50 mM glutamate, to stimulate radical formation. Twenty minutes later, α-phenyl-tert-butylnitrone (PBN; 100 mg/kg), selegiline (10 mg/kg), or saline was administered intraperitoneally. The glutamate perfusion produced marked two- to 2.5-fold increases in 2,3-DHBA content. Treatment with PBN significantly antagonized the rise of 2,3-DHBA level, indicating that PBN is a direct radical scavenger not only in vitro but also in vivo. Acute treatment with selegiline failed to reduce significantly the glutamate-induced radical formation. The acute experiments presented here do not support the suggestion that the neuroprotective effects of selegiline described in the literature are due to a potential hydroxyl radical scavenging property of the drug.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Journal of neural transmission 78 (1989), S. 231-247 
    ISSN: 1435-1463
    Keywords: Morphine ; conditioned effects ; hyperkinesia ; stereotyped behaviour
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Morphine (15 mg/kg i.p.) produces a biphasic effect: hypokinesia, followed by hyperkinesia and stereotyped behaviour. After repeated administration, the signs of the second phase more and more predominate. In the following study, it was evaluated, to which degree “classical” pharmacodynamic tolerance to hypokinesia or, alternatively, conditioning phenomena contribute to this shift. In particular, it was studied whether not only hyperkinesia but also stereotypies could occur as conditioned responses either in the presence or in absence of morphine. Rats were conditioned 8 times with morphine (15 mg/ kg i.p.) in the presence of various, defined conditioned stimuli (auditory, olfactory and tactile), another group was “pseudoconditioned”, i.e. they were exposed to the same treatment schedule of morphine and stimuli, but with no positive association between drug and stimuli, a third group (“naive rats”) was treated with saline instead of morphine, but exposed to the same stimuli as both other groups. All groups were tested for conditioned responses in the presence of the conditioned stimuli. One series of experiments was performed with saline after a break of 2 days after the end of the conditioning period, a second series was tested with saline after a break of 7 days, a third series with morphine (15 mg/kg i.p.) after a break of 2 days, a fourth series with the same dose of morphine after a break of 7 days. The results showed that when morphine was used after a break of 2 days, “classical” pharmacodynamic tolerance, but not conditioning phenomena could explain the shift in behaviour, whereas under the three other protocols described, some conditioned behavioural effects could be observed, either in presence or in absence of morphine, at least in part of the parameters used (locomotor activation, decrease in hypokinesia, sniffing, gnawing, rearing, but not in licking). Accordingly, development of pharmacodynamic tolerance and, to a lesser degree, conditioning contribute to the shift in behaviour after repeated administration of morphine. The conditioned effects could not be attributed to any alteration in striatal or mesolimbic dopamine turnover.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Cellular and molecular life sciences 29 (1973), S. 826-827 
    ISSN: 1420-9071
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Zusammenfassung Bei Mäusen erhöhte Pentobarbital den Serotoningehalt des Gehirns, ein Effekt, der sich durch eine Verminderung der Umsatzgeschwindigkeit bei unveränderter Synthese des Serotonins erklären lässt.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Cellular and molecular life sciences 29 (1973), S. 1365-1366 
    ISSN: 1420-9071
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Zusammenfassung Nach Hemmung der Dopaminsynthese beschleunigte Morphin bei Ratten die Abnahme der Dopaminkonzentration im Corpus striatum. Dieser Effekt, der durch Naloxon gehemmt wurde, lässt sich durch eine Erhöhung des Dopamin-Umsatzes im Corpus striatum unter Einfluss von Morphin erklären.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Cellular and molecular life sciences 32 (1976), S. 1558-1559 
    ISSN: 1420-9071
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Penfluridol, a neuroleptic with diphenylbutyl piperidine structure, blocked the dopamine-sensitive adenylate cyclase in homogenates of corpus striatum and substantia nigra of rats, probably by a competitive antagonism versus dopamine.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Archives of toxicology 35 (1976), S. 247-253 
    ISSN: 1432-0738
    Keywords: Dopamine receptors ; Adenyl cyclase ; Corpus striatum ; Ethanol withdrawal ; Barbiturate withdrawal ; Dopamin-Rezeptoren ; Adenyl-Cyclase ; Corpus striatum ; Äthanolentzug ; Barbituratentzug
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Nach wiederholter Gabe von Äthanol oder von Phenobarbital an Ratten wurden die Substanzen abgesetzt und dadurch charakteristische Entzugssymptome hervorgerufen. Weil beide Substanzen den Dopaminstoffwechsel im Gehirn beeinflussen, wurde die postsynaptische Empfindlichkeit gegenüber Dopamin in den Corpora striata während des Äthanol- bzw. Phenobarbital-Entzuges geprüft. Dies erfolgte, indem die Dopamin-empfindliche Adenylat-Cyclase in Homogenaten der Corpora striata untersucht wurde. Die Resultate zeigten eine leicht herabgesetzte Empfindlichkeit gegenüber Dopamin im Entzug von Äthanol oder Phenobarbital. Beide Substanzen beeinflußten, wenn sie in vitro den Homogenaten zugesetzt wurden, nicht die postsynaptische Empfindlichkeit gegenüber Dopamin. Im Falle des Dopamins konnte also nicht die Hypothese unterstützt werden, daß eine erhöhte postsynaptische Empfindlichkeit gegenüber den zugehörigen Neurotransmittern für Entzugs-Symptome nach chronischer Verabreichung von Substanzen, die körperliche Abhängigkeit hervorrufen, von Bedeutung ist.
    Notes: Summary Repeated administrations of ethanol and of phenobarbital to rats led to characteristic withdrawal symptoms when the drug had been stopped. Since both drugs affect brain dopamine metabolism, the postjunctional sensitivity to dopamine in the corpora striata was tested during ethanol or phenobarbital withdrawal. This was done by studying the dopamine-sensitive adenylate cyclase in homogenates of the corpora striata of ethanol- or phenobarbital-dependent rats. The results demonstrated a slight postjunctional subsensitivity to dopamine in withdrawal from both ethanol and phenobarbital. Both drugs, when added in vitro, did not affect the postjunctional sensitivity to dopamine. The results do not support the hypothesis, at least not in the case of dopamine, that a postjunctional supersensitivity to neurotransmitters is important for withdrawal symptoms after chronic administration of drugs inducing physical dependence.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 296 (1977), S. 249-254 
    ISSN: 1432-1912
    Keywords: Alpha-motoneurones ; Extensor ; Specific effects of narcotics ; Morphine ; Apomorphine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Specific effects of narcotics (opiates) were studied on rat extensor alpha-motoneurones. The animals were anaesthetized with halothane, artificially ventilated and immobilized with N,N′-diallyl nortoxiferinium-HCl. The alpha-motoneurones were activated by tetanic stimulation of the cut ipsilateral gastrocnemius-soleus (GS) nerve. Morphine (2 and 4 mg/kg) administered intravenously, significantly increased the frequency of reflex discharges. In most of the neurones tested, naloxone (0.25 mg/kg) given intravenously, abolished the effect of morphine. In some neurones, however, naloxone induced a further activation. The dose of naloxone employed was ineffective when given alone. The effect of morphine was mimicked by an intravenous injection of levorphanol (1 mg/kg), but not by an equimolar dose of the stereoisomer dextrorphan, which suggests that the activating effect on alpha-motoneurones is a specific one. An intraperitoneal injection of apomorphine (1 mg/kg) reduced the effect of morphine. The effect of narcotics on alpha-motoneurones parallels narcotic-induced catalepsy and muscular rigidity, with regard to dose-dependence as well as to the antagonism of naloxone and apomorphine, and suggests that both catalepsy and muscular rigidity are mainly due to an activation of extensor alpha-motoneurones. Since this activation can be inhibited by spinalization of the rats, it can be concluded that the activation is due to a supraspinal action of morphine, resulting in a decreased dopaminergic neurotransmission in the brain.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-2072
    Keywords: Apomorphine ; Conditioned dopaminergic activity ; Stereotyped behaviour ; Dopamine autoreceptors ; Dopamine metabolism ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We investigated whether pharmacological effects of the dopamine agonist apomorphine can be conditioned by establishing an association of apomorphine administration with exteroceptive cues. Apomorphine was repeatedly administered and subsequently, the rat was put into a test cage and exposed to an acoustic and an olfactory stimulus (“conditioned rats”). Control animals (“pseudoconditioned” rats) were treated with the same pharmacological schedule of apomorphine not temporally associated with the stimuli. On the test day, both groups were injected with saline and exposed to the stimuli described. The stereotyped behaviour produced by large doses of apomorphine (0.5 or 2.0 mg/kg SC), namely sniffing, licking and gnawing, could be conditioned in a pronounced way. During the conditioning period, a change in the stereotypies was observed with regard to the time-course (earlier occurrence) and to the character of the stereotypies (from sniffing to licking and gnawing), when 0.5 mg/kg apomorphine was used, but not with the dose of 2.0 mg/kg. The conditioned responses showed a relatively uniform distribution during the observation period with some increase towards the end of the observation period. Some signs produced by a low dose of apomorphine (0.07 mg/kg SC), namely hypomotility and ptosis, but not yawning, could also be conditioned, although in a less pronounced way. An intermediate dose of apomorphine (0.18 mg/kg SC) produced both signs observed after large doses and those observed after a small dose, occurring alternatingly. Both types of signs could be conditioned using this dosage. Conditioning did not alter striatal or mesolimbic dopamine turnover. These results suggest that only behavioural signs due to an activation of postsynaptic dopamine receptors, but also some symptoms produced by an activation of dopamine autoreceptors can be conditioned.
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