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Blythe B Holmes - One of the best experts on this subject based on the ideXlab platform.
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Opioid antagonists: indirect antagonism of morphine analgesia by spinal dynorphin A
Pharmacology Biochemistry and Behavior, 1993Co-Authors: F. Aksu, Blythe B HolmesAbstract:Abstract Naloxone and norbinaltorphimine when given ICV ICV to mice can antagonize IT morphine-induced analgesia indirectly by releasing spinal dynorphin A(1–17) (Dyn A). Dyn A produces an antianalgesic action against IT morphine. In the present study, drugs with varying amounts of opioid antagonist to agonist action (nalbuphine, Levallorphan, naltrexone, and naltrindole) were given ICV to determine whether they antagonized IT morphine-induced inhibition of the tail-flick response as an indication of spinal Dyn A release. Additional pharmacological tests were used as criteria for Dyn A release: a) Small doses of the opioid antagonists naloxone and norbinaltorphimine administered IT inhibited the antagonistic action; b) dynorphin antiserum given IT blocked the action of Dyn A; c) desensitization to the effect of Dyn A was produced by 3-h pretreatment with morphine, 10 mg/kg SC, or by pretreatment with the agents themselves. When given ICV, nalbuphine, Levallorphan, and naltrexone released Dyn A in the spinal cord to produce an antianalgesic effect. Naltrindole, a δ-receptor antagonist, did not release Dyn A. Dyn A release did not appear to involve δ-receptors. Thus, a number of opioid antagonists inhibit the analgesic action of opioid agonists indirectly through Dyn A release.
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Opioid antagonists: indirect antagonism of morphine analgesia by spinal dynorphin A
Pharmacology biochemistry and behavior, 1993Co-Authors: F. Aksu, Blythe B Holmes, James M. FujimotoAbstract:Naloxone and norbinaltorphimine when given ICV to mice can antagonize IT morphine-induced analgesia indirectly by releasing spinal dynorphin A(1-17) (Dyn A). Dyn A produces an antianalgesic action against IT morphine. In the present study, drugs with varying amounts of opioid antagonist to agonist action (nalbuphine, Levallorphan, naltrexone, and naltrindole) were given ICV to determine whether they antagonized IT morphine-induced inhibition of the tail-flick response as an indication of spinal Dyn A release. Additional pharmacological tests were used as criteria for Dyn A release: a) Small doses of the opioid antagonists naloxone and norbinaltorphimine administered IT inhibited the antagonistic action; b) dynorphin antiserum given IT blocked the action of Dyn A; c) desensitization to the effect of Dyn A was produced by 3-h pretreatment with morphine, 10 mg/kg SC, or by pretreatment with the agents themselves. When given ICV, nalbuphine, Levallorphan, and naltrexone released Dyn A in the spinal cord to produce an antianalgesic effect. Naltrindole, a delta-receptor antagonist, did not release Dyn A. Dyn A release did not appear to involve delta-receptors. Thus, a number of opioid antagonists inhibit the analgesic action of opioid agonists indirectly through Dyn A release.
F. Aksu - One of the best experts on this subject based on the ideXlab platform.
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Opioid antagonists: indirect antagonism of morphine analgesia by spinal dynorphin A
Pharmacology Biochemistry and Behavior, 1993Co-Authors: F. Aksu, Blythe B HolmesAbstract:Abstract Naloxone and norbinaltorphimine when given ICV ICV to mice can antagonize IT morphine-induced analgesia indirectly by releasing spinal dynorphin A(1–17) (Dyn A). Dyn A produces an antianalgesic action against IT morphine. In the present study, drugs with varying amounts of opioid antagonist to agonist action (nalbuphine, Levallorphan, naltrexone, and naltrindole) were given ICV to determine whether they antagonized IT morphine-induced inhibition of the tail-flick response as an indication of spinal Dyn A release. Additional pharmacological tests were used as criteria for Dyn A release: a) Small doses of the opioid antagonists naloxone and norbinaltorphimine administered IT inhibited the antagonistic action; b) dynorphin antiserum given IT blocked the action of Dyn A; c) desensitization to the effect of Dyn A was produced by 3-h pretreatment with morphine, 10 mg/kg SC, or by pretreatment with the agents themselves. When given ICV, nalbuphine, Levallorphan, and naltrexone released Dyn A in the spinal cord to produce an antianalgesic effect. Naltrindole, a δ-receptor antagonist, did not release Dyn A. Dyn A release did not appear to involve δ-receptors. Thus, a number of opioid antagonists inhibit the analgesic action of opioid agonists indirectly through Dyn A release.
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Opioid antagonists: indirect antagonism of morphine analgesia by spinal dynorphin A
Pharmacology biochemistry and behavior, 1993Co-Authors: F. Aksu, Blythe B Holmes, James M. FujimotoAbstract:Naloxone and norbinaltorphimine when given ICV to mice can antagonize IT morphine-induced analgesia indirectly by releasing spinal dynorphin A(1-17) (Dyn A). Dyn A produces an antianalgesic action against IT morphine. In the present study, drugs with varying amounts of opioid antagonist to agonist action (nalbuphine, Levallorphan, naltrexone, and naltrindole) were given ICV to determine whether they antagonized IT morphine-induced inhibition of the tail-flick response as an indication of spinal Dyn A release. Additional pharmacological tests were used as criteria for Dyn A release: a) Small doses of the opioid antagonists naloxone and norbinaltorphimine administered IT inhibited the antagonistic action; b) dynorphin antiserum given IT blocked the action of Dyn A; c) desensitization to the effect of Dyn A was produced by 3-h pretreatment with morphine, 10 mg/kg SC, or by pretreatment with the agents themselves. When given ICV, nalbuphine, Levallorphan, and naltrexone released Dyn A in the spinal cord to produce an antianalgesic effect. Naltrindole, a delta-receptor antagonist, did not release Dyn A. Dyn A release did not appear to involve delta-receptors. Thus, a number of opioid antagonists inhibit the analgesic action of opioid agonists indirectly through Dyn A release.
James M. Fujimoto - One of the best experts on this subject based on the ideXlab platform.
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Opioid antagonists: indirect antagonism of morphine analgesia by spinal dynorphin A
Pharmacology biochemistry and behavior, 1993Co-Authors: F. Aksu, Blythe B Holmes, James M. FujimotoAbstract:Naloxone and norbinaltorphimine when given ICV to mice can antagonize IT morphine-induced analgesia indirectly by releasing spinal dynorphin A(1-17) (Dyn A). Dyn A produces an antianalgesic action against IT morphine. In the present study, drugs with varying amounts of opioid antagonist to agonist action (nalbuphine, Levallorphan, naltrexone, and naltrindole) were given ICV to determine whether they antagonized IT morphine-induced inhibition of the tail-flick response as an indication of spinal Dyn A release. Additional pharmacological tests were used as criteria for Dyn A release: a) Small doses of the opioid antagonists naloxone and norbinaltorphimine administered IT inhibited the antagonistic action; b) dynorphin antiserum given IT blocked the action of Dyn A; c) desensitization to the effect of Dyn A was produced by 3-h pretreatment with morphine, 10 mg/kg SC, or by pretreatment with the agents themselves. When given ICV, nalbuphine, Levallorphan, and naltrexone released Dyn A in the spinal cord to produce an antianalgesic effect. Naltrindole, a delta-receptor antagonist, did not release Dyn A. Dyn A release did not appear to involve delta-receptors. Thus, a number of opioid antagonists inhibit the analgesic action of opioid agonists indirectly through Dyn A release.
H. D. Dellmann - One of the best experts on this subject based on the ideXlab platform.
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Levallorphan [(—)‐3‐Oxy‐N‐allyl‐morphinan‐tartrat], ein spezifischer Antagonist des Morphins und seiner Derivate
Zentralblatt für Veterinärmedizin, 2010Co-Authors: R. Fritsch, H. D. DellmannAbstract:Zusammenfassung Levallorphan [(—)-3-Oxy-N-allyl-morphinan-tartrat] wurde klinisch, besonders in Hinblick auf die Aufhebung der Polamivetwirkung untersucht. Bei Fehlen schadlicher Nebenwirkungen und groser Dosierungsbreite hebt es alle Polamivetwirkungen auf. Es normalisiert Atemfrequenz und -volumen, hebt die Analgesie auf und unterbricht den Schlafzustand oder vermindert ihn. Eine Kombination mit Polamivet, die die Atemdepression vermindert, die Narkosetiefe aber unbeeinflust last, konnte bis herunter zum Verhaltnis 1: 300 nicht gefunden werden. Ebenso konnte die Polamivetexzitation bei Katze und Rind nicht ohne gleichzeitige Aufhebung der Analgesie beseitigt werden. Levallorphan eignet sich in einer Dosis von 1/10 bis 1/20 der Polamivetdosis zur Unterbrechung der Polamivet- oder Megaphen-Polamivet-Betaubung beim Hund. Ebenso wirkt es gegen Morphin und Dolantin sowie gegen Vergiftungen mit Opiaten bei alien Tieren. In akuten Fallen wird Applikation je zur Halfte intravenos und intramuskular oder subkutan empfohlen. Summary Levallorphan [(—)-3-Oxy-N-allyl-morphine-tartrate], a specific antagonist of morphine and its derivatives This drug was studied clinically, with special relation to its neutralising effect on Polamivet (a synthetic narcotic like Polamidon = Methadon). The drug was very effective, produced no dangerous side-effects, and completely neutralised all the effects of Polamivet. It brought the respiration rate back to normal frequency and amplitude, removed the analgesia, and woke the animal completely or partially from its sleep. A combination of the drug with Polamivet which would reduce respiratory depression without affecting depth of narcosis could not be found, even at dilutions of 1: 300. Similarly one could not prevent the excitation which Polamivet causes in the cat and ox without simultaneously reducing the analgesia. Levallorphan, at a dosage of 1/10 to 1/20 that of Polamivet, is suitable for neutralising the narcotic effect of Polamivet or Megaphen combined with Polamivet in the dog. The drug is equally effective against morphine and Dolantin (Demerol) and against opiate poisoning in all animals. In acute cases half the drug is proposed to be given intravenously and the remainder intramuscularly or subcutaneously. Resume Le «Levallorphan» (tartrate de [—]-3-Oxy-N-allyl-morphinane un antidote specifique de la morphine et de ses derives Le «Levallorphan» (tartrate de [—]-3-oxy-N-allylmorphinane) fut etudie en clinique, particulierement son effet de neutralisation sur le «Polamivet». Sans que l'on ait observe d'action accessoire nuisible meme avec une grande latitude de dosage, il supprime tous les effets du «Polamivet». Il normalise la frequence et le volume respiratoires, supprime l'analgesie et interrompt l'anesthesie generale ou diminue sa profondeur. Une combinaison avec le «Polamivet» qui permettrait de diminuer la depression respiratoire sans intervenir sur l'etat de l'anesthesie generale ne put etre trouvee, meme en descendant jusqu'a un rapport de 1: 300. De meme, on ne put empecher l'excitation due au «Polamivet» chez le chat et le boeuf sans supprimer en meme temps l'analgesie. Le «Levallorphan» peut etre utilise a la dose de 1/10 a 1/20eme de la dose de «Polamivet» employee pour supprimer l'anesthesie generale au «Polamivet» ou au «Megaphen-Polamivet» chez le chien. Il est egalement actif contre la Morphine et la Dolantine ainsi que contre les intoxications par les derives de l'opium chez tous les animaux. Dans les cas aigus, on conseille son emploi moitie en injection intraveineuse, et moitie en injection intramusculaire ou sous-cutanee. Resumen Levalorfan (tartrato de [—]-3-oxi-N-alil-morfina), un antagonista especifico de la morfina y de sus derivados El levalorfan (tartrato de levo-3-oxi-N-alil-morfina) se estudio clinicamente, sobre todo con respecto a la supresion de la accion del polamivet. En ausencia de acciones secundarias perjudiciales y con una gran amplitud de dosificacion, suprime todas las acciones del polamivet. Normaliza la frecuencia y el volumen respiratorios, suprime la analgesia e interrumpe o disminuye el estado somnoliento. Bajando hasta la relacion 1: 300 no se pudo hallar la combinacion con el polamivet que disminuyese la depresion respiratoria, pero que dejase sin influenciar la profundidad de la narcosis. Igualmente tampoco se pudo eliminar en el gato y en los bovidos la excitacion debida al polamivet sin suprimir la analgesia al mismo tiempo. El levalorfan sirve para interrumpir en el perro la anestesia producida con el polamivet o megafenpolamivet, a una dosis de 1/10–2/10 de la de polamivet. Asimismo actua contra la morfina y la dolantina, al igual que en todos los animales contra las intoxicaciones por los opiaceos. En los casos agudos, se recomienda la aplicacion a partes iguales por las vias intravenosa e intramuscular o subcutanea.
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Levallorphan 3 oxy n allyl morphinan tartrat ein spezifischer antagonist des morphins und seiner derivate
Journal of Veterinary Medicine Series B-infectious Diseases and Veterinary Public Health, 2010Co-Authors: R. Fritsch, H. D. DellmannAbstract:Zusammenfassung Levallorphan [(—)-3-Oxy-N-allyl-morphinan-tartrat] wurde klinisch, besonders in Hinblick auf die Aufhebung der Polamivetwirkung untersucht. Bei Fehlen schadlicher Nebenwirkungen und groser Dosierungsbreite hebt es alle Polamivetwirkungen auf. Es normalisiert Atemfrequenz und -volumen, hebt die Analgesie auf und unterbricht den Schlafzustand oder vermindert ihn. Eine Kombination mit Polamivet, die die Atemdepression vermindert, die Narkosetiefe aber unbeeinflust last, konnte bis herunter zum Verhaltnis 1: 300 nicht gefunden werden. Ebenso konnte die Polamivetexzitation bei Katze und Rind nicht ohne gleichzeitige Aufhebung der Analgesie beseitigt werden. Levallorphan eignet sich in einer Dosis von 1/10 bis 1/20 der Polamivetdosis zur Unterbrechung der Polamivet- oder Megaphen-Polamivet-Betaubung beim Hund. Ebenso wirkt es gegen Morphin und Dolantin sowie gegen Vergiftungen mit Opiaten bei alien Tieren. In akuten Fallen wird Applikation je zur Halfte intravenos und intramuskular oder subkutan empfohlen. Summary Levallorphan [(—)-3-Oxy-N-allyl-morphine-tartrate], a specific antagonist of morphine and its derivatives This drug was studied clinically, with special relation to its neutralising effect on Polamivet (a synthetic narcotic like Polamidon = Methadon). The drug was very effective, produced no dangerous side-effects, and completely neutralised all the effects of Polamivet. It brought the respiration rate back to normal frequency and amplitude, removed the analgesia, and woke the animal completely or partially from its sleep. A combination of the drug with Polamivet which would reduce respiratory depression without affecting depth of narcosis could not be found, even at dilutions of 1: 300. Similarly one could not prevent the excitation which Polamivet causes in the cat and ox without simultaneously reducing the analgesia. Levallorphan, at a dosage of 1/10 to 1/20 that of Polamivet, is suitable for neutralising the narcotic effect of Polamivet or Megaphen combined with Polamivet in the dog. The drug is equally effective against morphine and Dolantin (Demerol) and against opiate poisoning in all animals. In acute cases half the drug is proposed to be given intravenously and the remainder intramuscularly or subcutaneously. Resume Le «Levallorphan» (tartrate de [—]-3-Oxy-N-allyl-morphinane un antidote specifique de la morphine et de ses derives Le «Levallorphan» (tartrate de [—]-3-oxy-N-allylmorphinane) fut etudie en clinique, particulierement son effet de neutralisation sur le «Polamivet». Sans que l'on ait observe d'action accessoire nuisible meme avec une grande latitude de dosage, il supprime tous les effets du «Polamivet». Il normalise la frequence et le volume respiratoires, supprime l'analgesie et interrompt l'anesthesie generale ou diminue sa profondeur. Une combinaison avec le «Polamivet» qui permettrait de diminuer la depression respiratoire sans intervenir sur l'etat de l'anesthesie generale ne put etre trouvee, meme en descendant jusqu'a un rapport de 1: 300. De meme, on ne put empecher l'excitation due au «Polamivet» chez le chat et le boeuf sans supprimer en meme temps l'analgesie. Le «Levallorphan» peut etre utilise a la dose de 1/10 a 1/20eme de la dose de «Polamivet» employee pour supprimer l'anesthesie generale au «Polamivet» ou au «Megaphen-Polamivet» chez le chien. Il est egalement actif contre la Morphine et la Dolantine ainsi que contre les intoxications par les derives de l'opium chez tous les animaux. Dans les cas aigus, on conseille son emploi moitie en injection intraveineuse, et moitie en injection intramusculaire ou sous-cutanee. Resumen Levalorfan (tartrato de [—]-3-oxi-N-alil-morfina), un antagonista especifico de la morfina y de sus derivados El levalorfan (tartrato de levo-3-oxi-N-alil-morfina) se estudio clinicamente, sobre todo con respecto a la supresion de la accion del polamivet. En ausencia de acciones secundarias perjudiciales y con una gran amplitud de dosificacion, suprime todas las acciones del polamivet. Normaliza la frecuencia y el volumen respiratorios, suprime la analgesia e interrumpe o disminuye el estado somnoliento. Bajando hasta la relacion 1: 300 no se pudo hallar la combinacion con el polamivet que disminuyese la depresion respiratoria, pero que dejase sin influenciar la profundidad de la narcosis. Igualmente tampoco se pudo eliminar en el gato y en los bovidos la excitacion debida al polamivet sin suprimir la analgesia al mismo tiempo. El levalorfan sirve para interrumpir en el perro la anestesia producida con el polamivet o megafenpolamivet, a una dosis de 1/10–2/10 de la de polamivet. Asimismo actua contra la morfina y la dolantina, al igual que en todos los animales contra las intoxicaciones por los opiaceos. En los casos agudos, se recomienda la aplicacion a partes iguales por las vias intravenosa e intramuscular o subcutanea.
Drake Morgan - One of the best experts on this subject based on the ideXlab platform.
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Contribution of individual differences to discriminative stimulus, antinociceptive and rate-decreasing effects of opioids: importance of the drug's relative intrinsic efficacy at the mu receptor.
Behavioural pharmacology, 1996Co-Authors: Drake MorganAbstract:Rats were trained to discriminate 3.0mg/kg morphine from water in a standard two-lever drug discrimination procedure and tested in a hot water tail-withdrawal procedure. When tested with morphine, fentanyl, buprenorphine and butorphanol, individual animals showed a three- to ten-fold difference in the lowest dose that substituted completely for morphine, whereas 30- to 1000-fold differences were obtained with nalbuphine and Levallorphan, respectively. Across repeated determinations, the dose-effect curves for morphine and nalbuphine remained relatively stable within an individual, suggesting that the profound individual differences with nalbuphine were not a consequence of variability in the dose-effect curve. In addition, despite the extremely shallow group dose-effect curves obtained with nalbuphine and Levallorphan, intermediate levels of drug-appropriate responding were not evidenced in individual animals. In the tail withdrawal procedure, the doses of morphine and fentanyl required to produce the maximal levels of antinociception varied by approximately three-fold across individual rats. With butorphanol and nalbuphine, differences across animals were greater than 30-fold and 300-fold, respectively, whereas with Levallorphan, substantial individual differences were observed in the maximal level of antinociception. Further analyses indicated that animals sensitive to the stimulus effects of nalbuphine and Levallorphan were also sensitive to the antinociceptive effects of nalbuphine, Levallorphan and butorphanol. In contrast to the individual differences obtained with the stimulus and antinociceptive effects of these opioids, the potency of these drugs for decreasing rate of responding was similar across animals. These findings indicate that the relative efficacy of an opioid at the mu receptor is an important determinant of individual differences in responsiveness to its stimulus and antinociceptive effects, but not to its rate-decreasing effects.