Characterization of the effects of (+/-)-meptazinol, its individual enantiomers and N-methyl meptazinol on food consumption in the rat.
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Both (+/-)-meptazinol (2 mg kg-1) and levorphanol (1 mg kg-1) produced hyperphagia over a 4 h period after intraperitoneal injection in free feeding rats during the daylight phase. The individual (+)- and (-)-enantiomers of meptazinol (2 mg kg-1 i.p.) induced comparable increases in cumulative food intake. N-methyl meptazinol (2-10 mg kg-1 i.p.), the quaternary analogue of meptazinol, produced no modification of food intake though it increased food consumption when injected intracerebroventricularly (10-100 micrograms per animal). Meptazinol and levorphanol hyperphagia was abolished by 1 mg kg-1 doses (i.p.) of the opioid antagonists naltrexone, naloxonazine and (-)-Mr 1452 but not by its (+)-enantiomer Mr 1453 which is not effective as an opioid antagonist. Intracerebroventricular administration of the delta-opioid antagonist ICI 154,129 (10 micrograms per animal) suppressed meptazinol but not levorphanol hyperphagia. It was concluded that meptazinol produces centrally mediated stereospecifically reversible hyperphagia through a mu-opioid receptor mechanism common to levorphanol, and also through delta-opioid receptor mechanism(s). (+info)
Stereospecific binding of the potent narcotic analgesic (3H) Etorphine to rat-brain homogenate.
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Etorphine, the most potent narcotic analgesic known, was labeled with tritium by catalytic exchange. This drug exhibits stereospecific, saturable binding to rat-brain homogenate. At saturation, the stereospecific binding is 0.1-0.15 pmol/mg of protein. Specific binding is inhibited high salt concentrations, sulfhydryl reagents, and proteolytic enzymes, but is unaffected by phospholipases A and C, sodium azide, sodium fluoride, and prostaglandins E(1) and E(2). Competition for binding of [(3)H]etorphine correlates with agonist and antagonist potencies. The stable, stereospecific binding of an active narcotic analgesic supports the existence of opiate receptors. (+info)
Properties of opiate-receptor binding in rat brain.
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[(3)H]Naloxone, a potent opiate antagonist, binds stereospecifically to opiate-receptor sites in rat-brain tissue. The binding is time, temperature, and pH dependent and saturable with respect to [(3)H]naloxone and tissue concentration. The [(3)H]naloxone-receptor complex formation is bimolecular with a dissociation constant of 20 nM. 15 Opiate agonists and antagonists compete for the same receptors, whose density is 30 pmol/g. Potencies of opiates and their antagonists in displacing [(3)H]naloxone binding parallel their pharmacological potencies. (+info)
Cellular and metabolic tolerance to an opioid narcotic in mouse brain.
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1. Running activity and brain levorphanol concentration were measured in nontolerant and tolerant mice given various doses of (3)H-levorphanol.2. The principal factor responsible for tolerance in the mouse is a loss of sensitivity to the narcotic drug at the cellular level in brain; despite adequate brain concentrations, the pharmacological effects are diminished or absent.3. There is also metabolic tolerance; a given dose establishes a lower brain concentration in tolerant than in non-tolerant animals.4. The two kinds of tolerance are distinguished here and the contribution of each is assessed. (+info)
Lethality of the morphinan isomers levorphanol and dextrorphan.
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Significantly different (P<0.05) LD(50) values were found in Swiss-Webster mice for levorphanol (73 mg/kg, i.p.) and dextrorphan (120 mg/kg, i.p.). A subcutaneous injection of naloxone 15 min before challenge prevented the lethal effect of an LD(98) of levorphanol, with ED(50) value of 1.36 mg/kg. Naloxone, in doses from 2 to 100 mg/kg, did not prevent death caused by 150 mg/kg of either dextrorphan or levorphanol. Levorphanol was lethal for mice pretreated with 10 mg/kg of naloxone, a dose sufficient to block opiate-specific lethal effects, but the LD(50) value was 109 mg/kg, in contrast to 73 mg/kg in the absence of naloxone. By the criteria of stereospecificity and naloxone blockade, levorphanol-induced mortality in mice is a typical opiate effect in the lower of the two dose ranges studied. At higher doses of levorphanol a non-specific effect supervenes, with an LD(50) value virtually the same as that of dextrorphan. (+info)
Steady-state measurement of the turnover of amino acid in the cellular proteins of growing Escherichia coli: existence of two kinetically distinct reactions.
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Turnover of cellular protein has been estimated in Escherichia coli during continuous exponential growth and in the absence of extensive experimental manipulation. Estimation is based upon the cumulative release into carrier pools of free leucine-1-(14)C over a number of time intervals after its pulsed incorporation into protein. Breakdown rates obtained with other labeled amino acids are similar to those obtained with leucine. Two kinetically separate processes have been shown. First, a very rapid turnover of 5% of the amino acid label occurs within 45 sec after its incorporation, most likely indicating maturative cleavages within the proteins after their assembly. A slower heterogeneous rate of true protein turnover follows, falling by 39% in the remaining proteins for each doubling of turnover time. At 36 C, the total breakdown rate of cellular protein is 2.5 and 3.0% per hr over a threefold range of growth rate in glucose and acetate medium, respectively. This relatively constant breakdown rate is maintained during slower growth by more extensive protein replacement, one fifth of the protein synthesized at any time in the acetate medium being replaced after 4.6 doubling times. Intracellular proteolysis thus appears to be a normal and integral reaction of the growing cell. The total rate equals minimal estimates obtained by others for arrested or decelerated growth but is kinetically more heterogeneous. Quantitatively proteolysis is not directly affected by growth arrestment per se as caused by alpha-methylhistidine, chloramphenicol, or uncouplers of oxidative phosphorylation, but qualitatively it can gradually become more homogeneous kinetically as a secondary event of starvation. Under more extreme conditions as with extensive washing, prolonged phosphorylative uncoupling, or acidification of the growth medium, the proteolytic rate can increase severalfold. (+info)
The effects of the morphine analogue levorphanol on leukocytes. Metabolic effects at rest and during phagocytosis.
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Studies on bacteria have suggested that morphine-like drugs have effects on the cell membrane. To determine the effect of this class of drugs on a mammalian cell, we selected the rabbit peritoneal exudate granulocyte, which undergoes striking membrane changes during phagocytosis. We examined the effect in vitro of the morphine analogue, levorphanol on phagocytosis and metabolism by granulocytes incubated with and without polystyrene particles or live Escherichia coli. Levorphanol (1 or 2 mmoles/liter) decreased: (a) acylation of lysolecithin or lysophosphatidylethanolamine in the medium (which is stimulated about two-fold during phagocytosis) both at rest (40%) and during phagocytosis (60%); (b) uptake of latex particles and Escherichia coli, as judged by electron microscopy; (c) killing of live Escherichia coli (10-fold); (d) (14)CO(2) production from glucose-1-(14)C during phagocytosis by at least 80%; (e) K(+) content of granulocytes (35%); (f) oxidation of linoleate-1-(14)C by 50%, and its incorporation into triglyceride by more than 80%. However, levorphanol stimulated 2 to 3-fold the incorporation of linoleate-1-(14)C or palmitate-1-(14)C into several phospholipids. Glucose uptake, lactate production, and adenosine triphosphate (ATP) content are not affected by the drug. Thus, levorphanol does not appear to exert its effects through generalized metabolic suppression. Removal of levorphanol by twice resuspending the granulocytes completely reverses all inhibition. In line with observations on bacteria, it appears that the complex effects of levorphanol on granulocytes may be due at least in part to an effect on the cell membrane. (+info)
Controlled comparison of the efficacy of fourteen preparations in the relief of postoperative pain.
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Thirteen analgesic drugs, four of them at two dose levels, four analgesics in combination with antagonist or neuroleptic agents, and saline have been evaluated simultaneously in the relief of postoperative pain. The method of assessment was designed to favour drugs which provided freedom from pain with minimum depression of consciousness. Only levorphanol 2 mg proved significantly superior to pethidine 100 mg, which was used as the standard reference drug. Oxycodone 10 mg, pentazocine 20 mg, and the morphine 10 mg and cyclizine 50 mg combination were the most successful of the remaining drugs. None of the drug combinations was significantly better than the analgesic drug given alone. (+info)