Tolerance to opioid narcotics, II. Cellular tolerance to levorphanol in mouse brain.
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Mice were made tolerant to a large dose of levorphanol, a congener of morphine. Then (3)H-levorphanol was given. The concentration of free, unchanged levorphanol in the brain water (ultrafiltrate) was found to be much higher than required to produce pharmacologic effects in nontolerant animals. The result indicates that tolerance arises from a diminished sensitivity to the drug at cellular or subcellular sites of drug action in the brain. (+info)
Stereospecific and nonspecific interactions of the morphine congener levorphanol in subcellular fractions of mouse brain.
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A METHOD IS DESCRIBED FOR ANALYZING THE ASSOCIATION OF THE OPIATE NARCOTIC LEVORPHANOL WITH BRAIN TISSUE INTO THREE COMPONENTS: nonsaturable, saturable nonspecific, and saturable stereospecific. The method may be of general applicability for the study of the interaction of drugs with body tissues. In mouse brain the stereospecific binding of levorphanol represents only 2% of the total association of drug with tissue, and it was found only in certain membrane fractions. The material responsible for the stereospecific binding might be the opiate receptor. (+info)
Quantitative studies on the antagonism by naloxone of some narcotic and narcotic-antagonist analgesics.
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1. Naloxone was used to study the antagonism of the analgesic effects of some narcotics (morphine sulphate, levorphanol tartrate, and methadone hydrochloride) and narcotic antagonists (pentazocine, cyclazocine, and nalorphine hydrochloride). The analgesic assay used was the mouse phenylbenzoquinone stretching test.2. The in vivo equivalent of a pA(2) value (apparent pA(2)) for naloxone was determined with each agonist. These values were found to be significantly larger with the narcotics than with the narcotic antagonists.3. The slopes in the apparent pA(2) plots were also found to be significantly different. It was concluded that this difference in slopes was probably not due to a lack of equilibrium in one of the two groups of analgesics.4. The results suggest that the narcotic and the narcotic-antagonist analgesics may inhibit stretching in this assay by interacting either with two different receptors or with the same receptor in a different manner. (+info)
Studies on the receptors involved in the action of the various agents in the phenylbenzoquinone analgesic assay in mice.
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1. Tolerance to the activity of several narcotic analgesics (morphine, levorphanol, and methadone) and several narcotic-antagonist analgesics (pentazocine, cyclazocine, and nalorphine) was studied in the mouse phenylbenzoquinone stretching test. Virtually complete tolerance was induced by chronic treatment with each of the narcotic agents, while no apparent tolerance was induced by the narcotic antagonists.2. In morphine-tolerant mice there was a high degree of cross-tolerance to the effects of not only the other narcotic drugs but also to those of the narcotic antagonists, acetylsalicylic acid, and physostigmine.3. The effects of morphine and pentazocine were antagonized by naloxone but not by atropine, while the effects of physostigmine were antagonized by atropine but not by naloxone. Neither atropine nor naloxone antagonized the effect of acetylsalicylic acid.4. The results of the tolerance study suggest that there is a fundamental difference in the consequences of receptor interaction for the narcotic and the narcotic-antagonist analgesics. Morphine-tolerant mice exhibit cross-tolerance non-specifically. The selectivity of naloxone and atropine differentiates the narcotic and narcotic-analgesics from the other two agents used in this analgesic test. (+info)
Antagonism by physostigmine of the "running fit" caused by levorphanol, a morphine congener, in mice.
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1. Drugs of the morphine type cause a stereotyped "running fit" in the mouse.2. The intensity and duration of this response are related to the dose.3. Measurement of this phenomenon serves as a good method for the quantitative comparison of drugs of this type and for the study of their antagonists.4. Intracerebral injection of physostigmine antagonized the "running fit" induced by a wide range of doses of levorphanol.5. The results are consistent with the hypothesis that drugs of the morphine type act by retarding the release of acetylcholine at some central cholinergic synapses. (+info)
Purification of the opiate receptor from rat brain.
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The opiate receptor was purified from a Triton-solubilized preparation of rat neural membranes by the use of affinity chromatography. The affinity gel was prepared by coupling 14-beta-bromoacetamidomorphine, a newly synthesized ligand, to omega-aminohexyl-Sepharose. After elution of the nonspecific proteins with 50 mM Tris (pH 7.5), the receptor proteins were eluted with 1 microM levorphanol or etorphine. NaDodSO4/polyacrylamide gel electrophoresis revealed three major proteins associated with the opiate receptor, having molecular weights of 43,000, 35,000, and 23,000. The purified receptor binds 10(-11) mol of dihydromorphine/per mg of protein, with a Kd of 3.8 X 10(-9) M. Other opiates, naloxone, and methionine-enkephalin, inhibit [3H]dihydromorphine binding in a manner similar to that observed with intact and solubilized neural membranes. (+info)
Opiate receptor mediation of ketamine analgesia.
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Previous workers have noted that analgesia produced by ketamine can be antagonized by the narcotic antagonist, naloxone. In order to elaborate further the apparent similarity between ketamine- and narcotic-induced analgesia, the authors examined the effects of ketamine in three standard test systems for the opiate receptor. In a radioligand binding assay using 3H-dihydromorphine, ketamine stereospecifically bound to opiate receptors in rat brain homogenate, (+) ketamine being 2-3 times more potent than the (-) enantiomer of ketamine. In a bioassay for the opiate receptor, using the longitudinal muscle-myenteric plexus of the guinea pig ileum, ketamine inhibited the twitch-like muscular contractions, as do narcotics. However, only the inhibitory effects of (+) ketamine, which in this system also was twice as potent as (-) ketamine, could be partially antagonized by naloxone, suggesting that this enantiomer is responsible for the opiate receptor-related effects of ketamine. In vivo, the authors found that ketamine displaces 3H-etorphine, a potent narcotic, from opiate receptors in regional areas of the mouse brain, especially in the thalamic region, but not in the cortex. The results suggest that a significant mechanism of ketamine-induced analgesia is mediated by opiate receptors. (+info)
Objective evaluation of dextromethorphan and glaucine as antitussive agents.
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Twenty-four inpatients affected by chronic cough completed a single-dose double-blind cross-over study of placebo, glaucine 30 mg and dextromethorphan 30 mg. The study was carried out using a balanced incomplete block design, each patient receiving two of the three experimental treatments. Objective evaluation of cough was ensured by means of a writing cough recorder. Coughs after dextromethorphan and glaucine were fewer than coughs after placebo: however only glaucine was significantly different from placebo in reducing coughs. Treatments were well tolerated: clinical results included a reduction in pulse rate after both dextromethorphan and glaucine , and a large number of patients reporting side effects after dextromethorphan administration. (+info)