Summary
The antinociceptive action of morphine and of a series of similar substances following intravenous and intraventricular administration was investigated by means of the tooth-pulp-test in rabbits; the relative effectiveness of the substances after the two methods of administration was compared with their lipid-solubility.
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1
Morphine was about 900 times as effective when administered intraventricu-larly than when injected intravenously; this difference was even more pronounced in the case of normorphine and (quaternary) N-methylmorphine, but was slightly less for dihydromorphine and hydromorphone. In the case of levorphanol, pethidine, etorphine, fentanyl and other synthetic analgesics, the difference in effectiveness between the two methods of administration was incomparably smaller (in the range of 1:10).
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2
The quotient effectiveness intravenous administration/effectiveness intraventricular administration bore a close relation to the lipid solubility of the substances derived from the partition coefficient (Pc) heptane/water and dichlor-ethane/water at pH 7.4. A similar correlation between Rf-values from thin-layer Chromatographie and this quotient was found. Morphine and its derivatives showed very low lipid-solubility (Pc heptane/water < 0.00001); that of the synthetic analgesics was higher, reaching Pc-values above 10. Thus it is concluded that the permeation of morphine and its hydrophilic derivatives into the CNS is impeded, whereas no important hindrance exists for permeation of the more lipophilic compounds having Pc’s above 0.01.
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3
Determination of the concentration of labelled substances in the brain (14C-morphine, 3H-dihydromorphine, 3H-fentanyl and 3H-etorphine) at the time of a defined antinociceptive effect confirmed this interpretation. In the case of morphine and dihydromorphine, brain concentrations were only 1/20 of the plasma level, while fentanyl and etorphine reached brain concentrations which were up to 10 times that in the plasma. Furthermore, the studies of concentration in the brain showed the gradation of effectiveness of the substances after intraventricular administration to be approximately equal to the gradation of their “intrinsic activity”.
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4
There was a close correlation between the lipid solubility of the substances and the rate of onset of their effect following intraventicular administration. This relation was much less pronounced after intravenous injection.
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5
The results are discussed in view of differences in the kinetics of distribution of the substances after intravenous and intraventricular application.
Über einen Teil der Ergebnisse wurde auf der Tagung der Deutschen Pharmakologischen Gesellschaft in Düsseldorf 1968 berichtet [Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 263, 199 (1969)].
Die Untersuchungen wurden von der Weltgesundheitsorganisation finanziell unterstützt.
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Literatur
Adler, T.K.: The comparative potencies of codeine and its demethylated metabolites after intraventricular injection in the mouse. J. Pharmacol. exp. Ther. 140, 155 (1963).
Ariens, E.J.: Receptor theory and structure-action-relationships. Advanc. Drug Res. 3, 235–285 (1966).
Beckett, A.H.: Analgesics and their antagonists: some steric and chemical considerations. J. Pharm. Pharmacol. 8, 848–859 (1956).
Blane, G.F., Dobbs, H.E.: Distribution of tritium labelled etorphine (M 99) and dihydromorphine in pregnant rats at term. Brit. J. Pharmacol. 30, 166–172 (1967).
Boura, A.L.A., Fitzgerald, A.E.: The pharmacology of N-(-cyclopropyl-methyl)-19-isopentyl-norovinol hydrochloride. A potent and long lasting central depressant. Brit. J. Pharmacol. 26, 301–321 (1966).
Braenden, O., Eddy, N., Halbach, H.: Synthetic substances with morphine-like effect. Relationship between chemical structure and analgesic action. Bull. Wld Hlth Org. 13, 923 (1955).
Bray, G.A.: A simple liquid scintillator for counting aquous solutions in a liquid scintillation counter. Analyt. Biochem. 1, 279–285 (1960).
Casy, A.F., Wright, J.: Ionisation constants and partition coefficients of some analgesically active 2-benzylbenzimidazole derivatives and related components. J. Pharm. Pharmacol. 18, 677–683 (1966).
Cube, B. von: Vergleich der analgetischen Wirkung morphinartiger Substanzen bei intravenöser und bei intraventrikulärer Applikation in Hinblick auf ihre Lipoidlöslichkeit. Inaug. Diss., Med. Fak. München 1969.
Diemer, K., Henn, R.: Kapillarvermehrung in der Hirnrinde der Ratte unter chronischem Sauerstoffmangel. Naturwissenschaften 6, 135–136 (1965).
Dobbing, J.: The blood-brain-barrier. Physiol. Rev. 41, 130 (1961).
Feldberg, W., Sherwood, S.C.: Behaviour of rats after intraventricular injection of eserine and DFP. J. Physiol. (Lond.) 125, 488 (1954).
Foster, R.S., Jenden, D.J., Lomax, P.: A comparison of the pharmacological effects of morphine and N-methylmorphine. J. Pharmacol. exp. Ther. 167, 185–195 (1967).
Hayashi, T., Karahashi, Y., Takeuchi, S.: Seizure action of quaternary ammonium compounds applied into cerebrospinal fluid of dogs. Keio J. Med. 14, 13–18 (1965).
Herz, A., Albus, K., Metys, J., Schubert, P., Teschemacher, Hj.: On the central sites of the antinociceptive action of morphine-like substances. In Vorbereitung (1970).
Albus, K., Metys, J., Schubert, P., Teschemacher, Hj. — Holzhäuser, H., Teschemacher, Hj.: Zentrale und periphere Wirkungen von Cholinomimetika und ihre Abhängigkeit von der Lipoidlöslichkeit. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 253, 280–297 (1966).
Albus, K., Metys, J., Schubert, P., Teschemacher, Hj. — Metyš, J., Schöndorf, N., Hoppe, S.: Über den Angriffspunkt der analgetischen Wirkung von Morphin. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path. 260, 143 (1968).
Albus, K., Metys, J., Schubert, P., Teschemacher, Hj. — Teschemacher, Hj., Hofstetter, A., Kurz, H.: The importance of lipid solubility for the central action of cholinomimetic drugs. Int. J. Neuropharmacol. 4, 207 (1965).
Hess, R., Teschemacher, Hj., Herz, A.: Über die Permeation von Xanthinderivaten in Gehirn und Liquor in Abhängigkeit von Lipoidlöslichkeit, Gewebsbindung und Stoffwechsel. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 261, 469–485 (1968).
Hoffmeister, F.: Tierexperimentelle Untersuchungen über den Schmerz und seine pharmakologische Beeinflussung. Aulendorf: Edition Cant. 1968.
Horlington, M., Lockett, M.: Antagonism between alkylated norcompounds of the morphine group injected intraventricularly to mice. J. Pharm. Pharmacol. 11, 415–420 (1959).
Hug, C.C.: Transport of narcotic analgesics by choreoid plexus and kidney in vitro. Biochem. Pharmacol. 16, 345–359 (1967).
Janssen, P.: Chemical structure and morphinomimetic activity. In: A. Soulairac, J. Cahn, and J. Charpentier, Eds. London: Academic Press 1968.
Johannesson, T.: Morphine and codeine. The analgesic effect in tolerant and non-tolerant rats. Acta pharmacol. (Kbh.) 29, 3 (1967).
Kupfferberg, H.J., Way, E.L.: Pharmacologic basis for the increased sensitivity of the newborn rat to morphine. J. Pharmacol. exp. Ther. 141, 105–112 (1963).
Lockett, M., Davis, M.M.: The analgesic action of normorphine administered intracisternally to mice. J. Pharm. Pharmacol. 10, 80–85 (1958).
Mahin, D.T., Lofberg, R.T.: A simplified method of sample preparation for determination of tritium, carbon 14 and sulfur 35 in blood or tissue by liquid scintillation counting. Analyt. Biochem. 16, 500–509 (1966).
Mellet, L., Woods, L.: Analgesia and addiction. Drug Res. 5, 159–267 (1963).
Portoghese, P.S.: A new concept on the mode of interaction of narcotic analgesics with receptors. J. Med. Chem. 8, 609–616 (1965).
Schubert, P., Teschemacher, Hj., Kreutzberg, G.H., Herz, A.: Autoradiographische Darstellung 14C-markierten Morphins nach intraventrikulärer und intracerebraler Injektion. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path. 260, 221 (1968).
— Intracerebral distribution patterns of morphine and morphine-like substances after intraventricular and local injection. In Vorbereitung (1970).
Scrafani, J.T., Hug, C.C.: Active uptake of dihydromorphine and other narcotic analgesics by cerebral cortical slices. Biochem. Pharmacol. 17, 1557–1566 (1968).
Takemori, A.E., Stenwick, M.W.: Studies on the uptake of morphine by choreoid plexus in vitro. J. Pharmacol. exp. Ther. 154, 586–594 (1966).
Tanaka, K., Kadowaki, Y.: The inhibitory effect of local anaesthetics on the excitement elicited by intraventricularly injected morphine. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 248, 9–14 (1964).
Teschemacher, Hj.: Permeationsverhalten morphinartiger Substanzen nachintraventrikulärer und intracerebraler Injektion (In Vorbereitung).
Way, E.L.: Brain uptake of morphine: Pharmacologie implications. Fed. Proc. 26, 1115–1118 (1967).
— Adler, T.K.: The pharmacologic implications of the fate of morphine and its surrogates. Pharmacol. Rev. 12, 383–446 (1960).
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Cube, B., Teschemacher, H., Herz, A., Hess, R. (1969). Permeation morphinartig wirksamer Substanzen an den Ort der antinociceptiven Wirkung im Gehirn in Abhängigkeit von ihrer Iipoidlöslichkeit nach intravenöser und nach intraventrikulärer Applikation. In: Habermann, E., et al. Naunyn Schmiedebergs Archiv für Pharmakologie. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-39718-3_343
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