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H W Kosterlitz

Publications and source records attributed to H W Kosterlitz.

At least 37 records · Page 2Linked to original sources
PubMed1977

Endogenous opioid peptides: multiple agonists and receptors.

Opioid peptides were assayed by inhibition of 3H-naloxone and 3H-leu-enkephalin binding in brain homogenates and by depression of contractions of the guinea pig ileum and mouse vas deferens. We conclude that the opioid peptidergic system has agonists of different characteristics which interact with more than one type of receptor.

Animals↗
PubMed1977

In vitro pharmacology of the opioid peptides, enkephalins and endorphins.

In the guinea-pig ileum methionine-enkephalin, normorphine and morphine are equipotent in depressing electrically evoked contractions; leucine-enkephalin has about 25% of the activity. The mouse vas deferens is more sensitive to the enkephalins which are 30 to 60 times more potent than morphine. Fragments of beta-lipotropin61-91 (beta-endorphin) having sequences up to LPH76 are more potent in the mouse vas deferens than in the guinea-pig ileum but beta-endorphin is about equipotent in the two preparations. None of the peptides has antagonist activity. Methionine-enkephalin and normorphine are equipotent in inhibiting [3H]-naloxone binding by homogenate of guinea-pig brain in the absence of Na+ while leucine-enkephalin has only 25% of this activity. In the guinea-pig ileum, naloxone antagonises normorhine and the enkephalins equally well whereas in the mouse vas deferens about ten times more naloxone is required for the enkophalins that for normorphine. Methionine-enkephalin depresses output of acetylcholine in the guinea-pig ileum and of noradrenaline in the mouse vas deferens.

Animals↗
PubMed1977

Opiate receptors and endogenous opioid peptides in tolerance and dependence.

The impact of the discovery of the endogenous opioid peptides, the enkephalins and endorphins, on our concepts of the mechanisms of tolerance to, and dependence on, opiates is discussed. After a brief survey of the chemistry of the opioid peptides, the possibility of an interaction between opiates and the peptides is considered and a hypothesis formulated. Experimental proof is presented as far as it has become available. The possible mechanisms involved in the development of tolerance and dependence for alcohol, barbiturates and opiates are compared briefly.

Adenylyl Cyclases↗
PubMed1977

Opioid peptides.

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Analgesia↗
PubMed1977

The distribution of methionine-enkephalin and leucine-enkephalin in the brain and peripheral tissues.

1 A method is described for the rapid extraction of opioid peptides from the brain and other tissues. The method is based on acid extraction of tissues followed by adsorption of the extract onto Amberlite XAD-2 resin. Elution with methanol separates the enkephalins and alpha-endorphin from beta-endorphin.2 Over 90% of the opioid peptide activity isolated from brain and gut of several species by our method was due to methionine- and leucine-enkephalin. In contrast, the major opioid peptide activity recovered from the pituitary was due to peptides of much greater mol. wt. than the enkephalins.3 An opioid peptide with properties unlike those of the known endorphins or enkephalins was present in brain extracts. This peptide, termed epsilon-endorphin, has an apparent mol. wt. of 700 to 1200; it constituted between 5 to 10% of the total opioid activity in our extracts.4 A differential assay of methionine- and leucine-enkephalin was made either by destroying methionine-enkephalin activity with cyanogen bromide or by separating the peptides by thin layer chromatography.5 The ratio of methionine-enkephalin to leucine-enkephalin varied greatly in different brain regions. The highest proportions of leucine-enkephalin were found in the cerebral cortex and hippocampus.6 Formaldehyde perfusion and fixation of the brain in vivo had no significant effect on the brain content of enkephalin, indicating that proteolytic breakdown is not a major problem in the extraction of these peptides.7 It is suggested that the enkephalins may have a neurotransmitter role in both brain and peripheral tissues and that methionine- and leucine-enkephalin may subserve separate neuronal functions.

Animals↗
PubMed1977

Peptides with morphine-like action in the brain.

The reasons which led to the search in the brain for substances with morphine-like actions actions are discussed. Two pentapeptides, methionineenkephalin and leucine-enkephalin, were isolated. The amino acid sequence of methionine-enkephalin occurs also in the pituitary prohormone beta-lipotropin, of which longer fragments (endorphins) of up to 31 amino acids exhibit strong morphine-like action. The physiological significance of these short and long opioid peptides is discussed, particularly with regard to their possible roles as neurotransmitter or neuromodulator. With regard to the mechanisms involved in the development of tolerance to and dependence on opiates, the importance of interaction between the endogenous opioid peptides and the exogenous opiate alkaloids is stressed. The possible therapeutic implications are discussed briefly.

Amino Acid Sequence↗
PubMed1976

Effects of physostigmine and electrical stimulation on the acetylcholine content of the guinea-pig ileum.

Incubation with physostigmine (7.7 muM) caused an approximately 2 fold increase in the acetylcholine content of the myenteric plexus--longitudinal muscle preparation of the guinea-pig ileum. This effect was due mainly to an increase in 'free' acetylcholine, which was directly assayable in either the homogenate after removal of cell debris or the supernatant fraction (100,000 g for 60 min) after subcellular fractionation. Acetylcholine output during stimulation at 0.017, 0.1 or 1 Hz was maintained for 60 min at a rate 2--4 times greater than the non-stimulated output; there was no change in content. At 10 HZ, output was high at the start of stimulation and then decreased continuously; there was a proportionate loss of mainly 'free' acetylcholine from the tissue. Mn2+, hexamethonium, morphine and noradrenaline, which depressed acetylcholine output during stimulation at 0.1 HZ, had no effect on the acetylcholine content nor did they affect the increase in acetylcholine content during incubation with physostigmine.

Acetylcholine↗
PubMed1975

Rates of onset and offset of action of narcotic analgesics in isolated preparations.

In isolated preparations of the myenteric plexus--longitudinal muscle of the guinea-pig ileum and the mouse vas deferens, the rates of onset and offset of action of narcotic analgesics are inversely related to lipid solubility; this effect is probably due to drug binding at secondary lipid-rich binding sites. These findings are in contrast to observations in vivo by A. Herz and his colleagues, who showed that the rates of onset of action and of recovery are directly related to lipid solubility because of the presence of lipid-rich barriers. In view of the opposite effects, an optimum may be expected when a drug has a degree of lipid solubility which ensures rapid penetration of the blood--brain barrier without seriously slowing down of receptor association and dissociation. From the interaction of rapidly acting quaternary antagonists, e.g. N-methylnalorphinium, with slowly acting agonists, e.g. methadone, it is concluded that at least a part of the receptor site is on the surface of the cell membrane, and the possibility of an allosteric agonist--antagonist interaction is considered.

Analgesics, Opioid↗
PubMed1975

An analysis of the phenomenon of acute tolerance to morphine in the guinea-pig isolated ileum.

1 The observations which Paton (1957) interpreted as 'acute tolerance' and 'dependence' have been confirmed for coaxially stimulated segments of guinea-pig ileum and extended to the contractions evoked by field stimulation in the myenteric plexus-longitudinal muscle preparation. Evidence is adduced that the morphine receptors of the myenteric plexus are not involved in the two phenomena. 2 The contraction of the longitudinal muscle depressed by low concentrations of morphine, or levorphanol, can be restored to control level not only by high concentrations of morphine but also by levorphanol and equally well by its (+)-isomer, dextrorphan, which does not fulfil the stereospecific requirements of the morphine receptor. Acetylcholine output was not increased. 3 When, after restoration of the twitch by high concentrations of morphine, the drug is washed out, contractions become depressed. This effect cannot be due to 'dependence' because either morphine or its antagonist, naloxone, restore the twitch again. 4 In the concentrations used, morphine, levorphanol and dextrorphan inhibit the cholinesterase of homogenates of the myenteric plexus-longitudinal muscle preparation by 10-15%. Since a concentration of physostigmine which causes a similar inhibition also restores the twitch, it is concluded that the described phenomena are best explained by the anticholinesterase effects of the drugs.

Acetylcholine↗
PubMed1975

Effect of morphine on adrenergic transmission in the mouse vas deferens. Assessment of agonist and antogonist potencies of narcotic analgesics.

1. Morphine inhibits the electrically evoked (0.1-0.15 Hz, 1 ms) contractions of the longitudinal muscle of the mouse vas deferens but not of the rabbit, guinea-pig, rat, cat, hamster or gerbil. This effect is stereospecific and is antagonized by naloxone or naltrexone. 2. Normorphine is equiactive with morphine but its effects are more rapid in onset and decline. 3. In the mouse vas deferens, the resting outflow of tritium-labelled catecholamines is unaffected by morphine. The electrically evoked outflow is depressed by morphine or normorphine in a dose-dependent manner. The ID50 for inhibition of contraction and for depression of outflow is 0.5 muM. 4. The relative agonist potencies of compounds without antagonist component (codeine, pethidine, morphine, normorphine, heroin, levorphanol, Ba-20227, etorphine) show good correlation with the relative agonist potencies determined in the guinea-pig ileum and for analgesia in man. 5. For compounds with dual agonist and antagonist properties, the dose-response curves for agonist activity are shallow. When the lowest concentrations giving a depression of the contraction of the mouse vas deferens are used, a good correlation is obtained with the guinea-pig ileum. 6. The relative antagonist potencies of naloxone, nalorphine, levallorphan, and cyclazocine agree well with those obtained in the guinea-pig ileum; these, in turn, correlate well with the values obtained in the morphine-dependent monkey. 7. The fact that the agonist effects of drugs with dual agonist and antagonist action show little or no dependence on concentration, makes the mouse vas deferens particularly suitable for the assay of assay of antagonist activity. 8. As an assay preparation, the mouse vas deferens is less robust and consistent in its responses than the guinea-pig ileum.

Analgesics, Opioid↗
PubMed1975

Assessment in the guinea-pig ileum and mouse vas deferens of benzomorphans which have strong antinociceptive activity but do not substitute for morphine in the dependent monkey.

1 Four benzomorphans which have potent antinociceptive activity in the hot-plate and writhing tests in the mouse but do not suppress or precipitate withdrawal symptoms in the morphine-dependent monkey, have been examined for their pharmacological actions in the guinea-pig ileum and mouse vas deferens. 2 In the guinea-pig ileum their agonist potencies are 1.5 to 400 times greater than that of normorphine of morphine whereas in the mouse vas deferens their potencies relative to morphine are 0.3 to 100. They exhibit no antagonist activity in either preparation. Benzomorphans which substitute for morphine in the morphine-dependent monkey do not show such differences between their relative potencies in the guinea-pig ileum and mouse vas diferens. 3 The relative potencies of the four benzomorphans to inhibit stereospecific [3H]-dihydromorphine binding by membrane fragments from rat brain, are more closely related to their relative agonist potencies in the mouse vas deferens than to those found in the guinea-pig ileum. 4 In order to antagonize the agonist actions of these benzomorphans, naloxone is required in concentrations which are 3 to 7 times higher than those needed for the antagonism of normorphine or morphine or of benzomorphans which suppress abstinence in morphine-dependent monkeys. 5 It may be possible to use the three assays, namely, ratio of relative agonist potency in mouse vas deferens to that in guinea-pig ileum, ratio of relative agonist potency to relative affinity to opiate receptors and the concentration of nalozone required for antagonism, for the prediction of the potential of new compounds to produce physical dependence.

Analgesics, Opioid↗