Showing papers on "Opiate published in 1975"
TL;DR: Interactions between endogenous enkephalin and exogenous opiate at the opiate receptor are discussed as a possible basis of tolerance and dependence caused by chronic administration of opiates.
263 citations
TL;DR: The isolation of a morphine-like peptide which may be a central nervous system neurotransmitter sheds light on normal brain mechanisms regulating pain and emotion.
Abstract: Recent biochemical identification of the receptor site for pharmacological actions of opiates helps elucidate how these drugs relieve pain, elicit euphoria and ‘addiction’, and provides simple, direct approaches to developing potentially non-addicting analgesics. The isolation of a morphine-like peptide which may be a central nervous system neurotransmitter sheds light on normal brain mechanisms regulating pain and emotion.
178 citations
TL;DR: The hypothesis that some features of hypnotic analgesia are mediated through neuronal pathways activating specific opiate receptors in brain are not confirmed and the opiate antagonist naloxone had no effect on hypnotics analgesia in three subjects.
Abstract: Hypnotic analgesia in some respects resembles opiate analgesia. We tested the hypothesis that some features of hypnotic analgesia are mediated through neuronal pathways activating specific opiate receptors in brain. The opiate antagonist naloxone had no effect on hypnotic analgesia in three subjects. Thus, the hypothesis was not confirmed.
125 citations
Journal Article•
TL;DR: It is proposed that morphine exerts some of its central nervous actions by first interfering with dopamine-mediated synaptic transmission and then initiating compensatory changes that superficially resemble denervation supersensitivity which may underlie the excitatory actions of morphine.
Abstract: We have studied the interactions between morphine and a dopamine-blocking agent (haloperidol) and a dopamine precursor, L-3,4-dihydroxyphenylalanine (L-dopa). We found that haloperidol potentiated morphine-induced analgesia and enhanced morphine tolerance. Morphine-tolerant mice exhibited enhanced sensitivity to the locomotor excitatory actions of L-dopa. We propose that morphine exerts some of its central nervous actions by first interfering with dopamine-mediated synaptic transmission and then initiating compensatory changes that superficially resemble denervation supersensitivity. These compensatory changes may underlie the excitatory actions of morphine.
103 citations
TL;DR: It was suggested that there may be common pharmacological mechanisms involved in both positive reinforcement and aversive conditioning by drugs of the opiate class.
Abstract: In Experiment 1, 4 doses of morphine and 4 doses of naloxone were tested for their ability to induce a conditioned aversion to saccharin in rats. Morphine was much more potent than naloxone which had only weak effects at the highest dose (12.96 mg/kg). Based on the determinations of Experiment 1, doses of 0.096, 0.96 and 0.6 mg/kg of morphine in a second experiment. The highest dose of naloxone was an effective antagonist of morphine-induced aversion. The antagonism was incomplete, but this may have reflected the particular dose combinations that were employed. Although 12.96 mg/kg of naloxone induced only a weak conditioned aversion to saccharin in Experiment 1, 9.6 mg/kg had a substantial effect in Experiment 2. Thus naloxone was itself an agent of aversive conditioning at a dose which significantly antagonized the aversive effects of morphine. Because of the successful demonstraion of antagonism, it was suggested that there may be common pharmacological mechanisms involved in both positive reinforcement and aversive conditioning by drugs of the opiate class.
96 citations
TL;DR: A very slight hypothermic effect was observed at a naloxone dose sufficient to block the opiate receptors, and the magnitude of the effect was so small as to lend little support to the hypothesis that an endogenous opioid plays a significant role in temperature regulation in the rat.
94 citations
TL;DR: Differentiation of this response using reserpine and naloxone indicates the possibility of calcium pools in the central nervous system.
Abstract: —
The in vivo administration of a single dose of morphine produces a decrease of tissue calcium in the rat brain. This decrease is observed to be linear, dose-dependent, time-dependent and to occur to an equal degree in 8 discrete brain regions. This effect of morphine is blocked by naloxone and exhibits a high degree of sterospecificity. The reserpine induced decrease of brain calcium was not antagonized by naloxone. Differentiation of this response using reserpine and naloxone indicates the possibility of calcium pools in the central nervous system.
The results are discussed in terms of a specific effect of opiate drugs and the role of calcium in opiatereceptor interactions.
77 citations
TL;DR: The sleep of 6 opiate addicts was studied for 11 nights during 3 phases of a chronic morphine cycle, which produces signs of a small but persistent sleep disturbance that contrasts with the sedation seen during chronic methadone.
Abstract: The sleep of 6 opiate addicts was studied for 11 nights during 3 phases of a chronic morphine cycle. The control phase consisted of 5 consecutive nights before morphine administration. The induction phase consisted of 1 night at 21–36 days after the onset of morphine administration, when the daily dose was 140–220 mg. The stable dose phase consisted of 5 consecutive nights after the subjects had received 240 mg of morphine daily for 8–19 weeks. No sleep could be studied during the withdrawal phase. Sleep was continuously monitored with EEG, EMG and EOG.
70 citations
TL;DR: The present results suggest that the stimulus properties of morphine represent typical opiate effects.
Abstract: The present investigation sought (a) to establish the efficacy of morphine and ethanol as discriminative stimuli when each is paired with the administration of saline and (b) to compare, in a qualitative sense, the stimulus properties of the two drugs. Additional experiments examined the effects of treatment with naloxone or l-propranolol upon morphine and ethanol-mediated discriminated responding. Finally, the stereospecificity of the stimuli produced by morphine was determined by a comparison, in morphine-trained rats, of levorphanol and dextrorphan. Discriminated responding developed rapidly in both the morphine and ethanol groups. In tests in which ethanol was administered to morphine-trained animals and vice versa, no similarity to stimulus properties was apparent. Antagonism of discriminated responding induced by morphine and ethanol was attempted using naloxone and l-propranolol. Naloxone blocked the actions of morphine but was without effect upon ethanol. No evidence of antagonism of either drug by propranolol was found. When a range of doses of levorphanol (0.1-3 mg/kg) and dextrorphan (3-100 mg/kg) was tested in morphine trained animals, only levorphanol was able to substitute for morphine. The present results suggest that the stimulus properties of morphine represent typical opiate effects.
63 citations
TL;DR: It is indicated that morphine-abstinence effects express increased activity of a central cyclic AMP mechanism and naloxone can potently stimulate behavior in animals not treated with any opiate drug.
60 citations
TL;DR: It is reported that binding of opiate receptors is much more sensitive to degradation by protein reagents which are known to modify sulphydryl groups than is binding by opiate antagonists, suggesting that distinct binding sites exist for agonists and antagonists, although they may both be on the same receptor.
Abstract: OPIATE antagonists differ from opiates only by the replacement of the N-methyl substituent with an N-allyl, N-cylcopropylmethyl or related group. Antagonists can reverse the pharmacological effects of opiates and so are important in the treatment of opiate overdose. Drugs that combine agonist and antagonist activities have potential as relatively nonaddicting analgesics. Although their mutual pharmacological antagonism indicates that they act at the same binding site, pharmacological discrepancies have prompted speculation that agonist and antagonist binding sites are separate1,2. Biochemical study of receptor binding3–16 has shown that although opiate agonists and antagonists compete for the same receptor3,4, there are differences in the way they interact with them7,10. Physiological concentrations of sodium enhance the binding of 3H-antagonists but reduce that of 3H-agonists. Sodium diminishes the ability of pure agonists to inhibit binding of 3H-naloxone to the receptor, but has little influence on inhibitory effects of pure antagonists and intermediate effects on those of combination agonist–antagonist drugs. The molecular basis for these differences, however, is unclear. As a first step in this direction we now report that binding of opiate receptors is much more sensitive to degradation by protein reagents which are known to modify sulphydryl groups than is binding by opiate antagonists. This suggests that distinct binding sites exist for agonists and antagonists, although they may both be on the same receptor.
TL;DR: Compared a variety of well known behavioral actions of morphine across four strains of laboratroy mice, it was found that analgesia and drug-seeking did not vary greatly among strains, although some statistically significant differences were found.
TL;DR: It is concluded that morphine probably acts to reduce the excitability of a class of myenteric plexus neurons, perhaps by hyperpolarizing or stabilizing the membrane potential.
TL;DR: A mass fragmentographic method for simultaneous measurement of unlabeled and deuterium labeled methadone in human plasma is described and will be of value in the study of Methadone pharmacokinetics in the steady state and in other in vivo situations where multiple drug pools must exist.
Abstract: A mass fragmentographic method for simultaneous measurement of unlabeled and deuterium labeled methadone in human plasma is described. This specific method has a lower sensitivity of about 16 pmol/ml with a coefficient of variation of less than 4%. The usefulness of the method was evaluated in studies on opiate dependent subjects undergoing methadone maintenance treatment. In one application methadone-d3 was given as a pulse dose during continuous treatment with unlabeled methadone and plasma levels of both species followed by mass fragmentography. The method will be of value in the study of methadone pharmacokinetics in the steady state and in other in vivo situations where multiple drug pools must exist.
TL;DR: Brain levels of 3H-serotonin and of its main metabolite, 5-hydroxyindoleacetic acid, were significantly elevated and an increase in the activity of tryptophan hydroxylases was more pronounced in the forebrain than in the brain stem.
Journal Article•
TL;DR: It is concluded that the slice is the preferable preparation for the in vitro estimation of opiate receptor binding and that chronic morphine treatment alters the binding of morphine to brainstem.
Abstract: The binding of morphine to brainstem slices was studied with nanomolar concentrations of (3H)-morphine. Rat brainstem slices were incubated at 35 degrees C and immediately homogenized. Bound morphine was estimated using Millipore filters to separate unbound morphine. Binding of labelled morphine was markedly inhibited by either non-labelled morphine or naloxone, indicating that a substantial portion of the binding is saturable. The saturable morphine binding to slices was significantly greater than that to brainstem tissue homogenized prior to incubation with morphine, whereas non-saturable binding was the same in both preparations. Saturable binding of morphine to brainstem slices was lower in rats rendered tolerant to morphine (using pellet implantation) than in non-tolerant controls. It appears that chronic morphine treatment decreases the affinity of the opiate receptor for morphine. It is concluded that the slice is the preferable preparation for the in vitro estimation of opiate receptor binding and that chronic morphine treatment alters the binding of morphine to brainstem.
TL;DR: Tolerance to injected morphine cannot be explained by reduced affinity of the drug for the opiate receptor, and it is suggested that this new receptor is involved in tolerance to injection morphine as well as some aspects of the withdrawal syndrome.
TL;DR: The results indicate that the number of neurons excited by naloxone is increased in m.
TL;DR: The study shows that psychological and socio‐environmental factors make trials on drug treatment of opiate addicts almost impossible to carry out.
Abstract: On the hypothesis that drug addiction may be due to "masked depression", lithium was administered to 20 opiate addicts. Only nine patients took the lithium carbonate tablets for more than a few weeks; during this period they seemed to abstain from taking opiates. After 1 year, all the patients were off lithium and most of them again took opiates. Due to lack of cooperation on the part of the patients, the observations can neither confirm nor refute our hypothesis. The study shows that psychological and socio-environmental factors make trials on drug treatment of opiate addicts almost impossible to carry out.
Journal Article•
TL;DR: The results show that high doses of naloxone can duplicate some effects of morphine or meperidine but at low doses it antagonizes the effects of the full agonists, which would suggest that n aloxone is a partial agonist with a very low intrinsic activity.
Abstract: In drug interaction studies on intact mice it was found that naloxone (3mumoles/kg) antagonized the general central nervous system depressant effects of morphine or meperidine Higher naloxone doses (03 and 04 mmoles/kg), like the fullagonists, potentiated the loss of the righting reflex produced by phenobarbital Naloxone (03 to 14 muM) antagonized the depressant effects of morphine or meperidine on the compound action potential of frog's sartorius muscles in vitro Higher naloxone concentration (ED20=03 mM, ED100=30mM), like the full agonists, depressed action potential production These results show that high doses of naloxone can duplicate some effects of morphine or meperidine but at low doses it antagonizes the effects of the full agonists This would suggest that naloxone is a partial agonist with a very low intrinsic activity These results also indicate that there are opiate drug receptors on excitable cell membranes and that drug activation of these receptors inhibits action potential production
TL;DR: Electroencephalographic, locomotor, and analgesic responses were studied in two strains of inbred mice implanted with epidural cortical electrodes and the septal area is implicated in morphine-induced analgesia but not in the locomotor responses or in the brain electrical responses to the opiate.
TL;DR: Opiates displaced [3H]-testosterone in relation to their pharmacological potencies from binding sites on rat liver microsomes, supporting the hypothesis that opiate action is mediated through steroid hormone receptors.
TL;DR: It is evident from these studies that several drugs can unspecifically modify the pharmacologic effects of opiates and that they could be useful tools to further characterize the opiate receptor.
TL;DR: It is evident from the data obtained from the study that animal tests allow the prediction of expectable analgetic potencies of new compounds in man.
TL;DR: When morphine HCI was administered via intraventricular cannulae following pretreatment with propranolol given intraperitoneally in rats performing free operant (sidman) avoidance, the anti-avoidance effects of the opiate were also attenuated, suggesting that previous results cannot be attributed solely to reduced concentration of morphine at CNS site(s) of action.
Abstract: Pretreatment with propranolol HCl resulted in a substantial reduction in the amount of 14C-morphine found in blood plasma, neostriatum plus adjacent tissue, pons-medulla, midbrain, cerebral cortex and cerebellum 25 min after IP injection of the labelled morphine. Previous observations, demonstrating attenuation of behavioral effects of morphine following pretreatment with propranolol, might have been due to a decrease in peripheral and/or central levels of morphine. However, when morphine HCl (10–20 μM) was administered via intraventricular cannulae following pretreatment with propranolol given intraperitoneally in rats performing free operant (Sidman) avoidance, the anti-avoidance effects of the opiate were also attenuated. Hence, previous results cannot be attributed solely to reduced concentration of morphine at CNS site(s) of action.
Book•
15 Jun 1975