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Biomedical subjects

H W Kosterlitz

Publications and source records attributed to H W Kosterlitz.

At least 109 records · Page 6Linked to original sources
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

The effects of morphine on the release of noradrenaline from the cat isolated nictitating membrane and the guinea-pig ileum myenteric plexus-longitudinal muscle preparation.

1. Electrical field stimulation of either the cat isolated nictitating membrane or the guinea-pig ileum myenteric plexus-longitudinal muscle preparation caused the release of noradrenaline into the bathing medium. 2. In the cat nictitating membrane, the output per pulse of noradrenaline was constant at frequencies of stimulation from 0.5 to 15 Hz. In the guinea-pig myenteric plexus preparation the output per pulse of noradrenaline increased as the frequency of stimulation was increased from 2 to 16 Hz. 3. Phenoxybenzamine (29.3 muM) caused a marked increase in the noradrenaline output from both the cat nictitating membrane and guinea-pig myenteric plexus preparations. 4. Morphine (0.13-8 muM) inhibited the contractions of the cat nictitating membrane caused by electrical stimulation. This effect was greater at low (1Hz) than at high (15Hz) frequencies of stimulat The site of action is at the nerve-smooth muscle junction. 5. The action of narcotic analgesic drugs on the cat nictitating membrane showed stereospecificity. Naloxone (0.1 muM) reversed the inhibition caused by normorphine (3.2 muM). 6. Morphine (3 muM) reduced the noradrenaline output from the cat nictitating membrane stimulated at 1 Hz but not at 15 Hz. At 1 Hz, the inhibition of noradrenaline output by normorphine (muM) was reversed by naloxone (0.25 muM). 7. Morphine (1.5 muM) did not alter the noradrenaline output from the guinea-pig myenteric plexus preparation stimulated at 2 or 16 Hz.

Animals↗
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↗
PubMed1975

Narcotic agonist and antagonist potencies of a homologous series of N-alkyl-norketobemidones measured by the guinea-pig ileum and mouse vas deferens methods.

The narcotic agonist and antagonist potencies of the series of N-alkyl-norketobemidones from norketobemidone to decylnorketo-bemidone have been determined. The values obtained in the electrically stimulated preparations of the guinea-pig ileum and the mouse vas deferens are closely correlated. The agonist potencies observed in the guinea-pig ileum agree well with those found in the mouse hot-plate test (Oh-ishi & May) and those obtained by determining the inhibition of naloxone binding in brain homogenates (Wilson, Rogers, Pert & Snyder). The antagonist potencies in the guinea-pig ileum and, to a lesser extent, those in the mouse vas deferens agree with the values obtained in the morphine-dependent monkey.

Animals↗
PubMed1975

In vitro models in the study of structure-activity relationships of narcotic analgesics.

Evidence has been adduced for the view that the morphiness receptor or receptors in the myenteric plexus of guinea pig ileum are very similar to the brain receptors that mediate the analgesic action of the narcotic alagesics. Such an in vitro model is very suitable for the study of structure-activity relationships because the angonist and antagonist activities of compounds can readily be assessed. One example is the investigation of the effects of changes at the N atom. Another point of interest is the role of substitutions at the C14 atom in morphine and morphinans. Such alterations in structure may have a profound effect on the relative agonist and antagonist activities and may convert a drug with dual agonist and antagonist actions into an antagonist devoid of agonist action.

Analgesics, Opioid↗
PubMed1972

A new example of a morphine-sensitive neuro-effector junction: adrenergic transmission in the mouse vas deferens.

The isolated mouse vas deferens possesses an adrenergic excitatory motor innervation which can be inhibited by low concentrations of morphine (ID50=0.5 muM). This effect of morphine is mediated by specific receptors which are blocked by naloxone. Activation of the morphine receptors inhibits noradrenaline release. It is concluded that adrenergic neurotransmission in the mouse vas deferens differs in some important way from that at the more common, morphine-insensitive, adrenergic junctions.

Animals↗