Non-participation of Blood-cerebrospinal Fluid-barrier in the Development of Tolerance to the Analgesic Effect of Morphine in Mice.

‰H –ì Žõ • E ‹à OEË —m • EŠp‰i • • • v Recently, Kase (1-2) put forward the remarkable hypothesis that the development of tolerance to morphine is due to the changes of blood-cerebrospinal fluid-barrier. This hypothesis was based on the experimental results that morphinized dogs lost their acquired tolerance to morphine by elec trical shock or chemical seizures resulting from the alteration of blood-cerebrospinal fluid-barrier, and that repeated intracisternal injection of morphine into dogs failed to develop the tolerance. However, since his experiments were done only with the antitussive effects of morphine it seemed worthwhile to investigate whether his hypothesis is applicable to other effects of morphine, The male white mice of ddO strain weighing about 20 g were used in these experiments. Mor phinized mice were made 1) by subcutaneous injections of morphine twice daily in increasing dose from 20 mg/kg to 80 mg/kg body weight or 2) by intracisternal injections of morphine daily increas ing dose from 50 ug/kg to 150 ug/kg for 2 weeks. The control groups were given injections of saline for the same period. Electroshock seizures were induced by applying 60 cps current of 15 mA for 0.2 sec to conjunc tive sacs of mice. Metrazol shock was produced by injecting 60 mg/kg of Metrazol intraperitoneally into animals. Intracisternal injections were made as described by Horlington and Lockett (3). Anal gesia was measured by both the D'Amour-Smith method and electric stimulation method. In the first experiments, both control and subcutaneously morphinized mice were subjected to the Metrazol or electroshock. Twenty-four hours after the convulsion the analgesia caused by 5 mg/kg of subcutaneous morphine was evaluated.