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Permeation morphinartig wirksamer Substanzen an den Ort der antinociceptiven Wirkung im Gehirn in Abhängigkeit von ihrer Iipoidlöslichkeit nach intravenöser und nach intraventrikulärer Applikation

  • B. Cube
  • Hj. Teschemacher
  • A. Herz
  • R. Hess
Chapter

Schlüsselwörter

Morphinartige Substanzen Permeation in das Gehirn Intraventrikuläre Applikation „Intrinsic activity” Lipoidlöslichkeit 

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.
  1. 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).

     
  2. 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.

     
  3. 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”.

     
  4. 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.

     
  5. 5

    The results are discussed in view of differences in the kinetics of distribution of the substances after intravenous and intraventricular application.

     

Key-Words

Morphine-Like Substances Permeation into Brain Intraventricular Application “Intrinsic Activity” Lipid-Solubility 

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Copyright information

© Springer-Verlag Berlin Heidelberg 1969

Authors and Affiliations

  • B. Cube
    • 1
  • Hj. Teschemacher
    • 1
  • A. Herz
    • 1
  • R. Hess
    • 1
  1. 1.Max-Planck-Institut für PsychiatrieMünchen 23Deutschland

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