Abstract

The impact on the unanesthetized rabbit's brain of morphine hydrochloride, levorphan and levallorphan, (a drug antagonizing both the respiratory depression and the analgesia produced by morphine) was determined electrographically. The topical antagonism between the morphine-levorphan group and levallorphan at various low doses (0.2 to 0.8 mgm./kgm. i.v.) and higher doses (6 to 15 mgm./kgm. i. v.) has been confirmed electrographically.

Morphine and levorphan evoke a sleep-like, generalized slow wave activity with drowsiness, when higher doses are given (20-40 mgm./kgm. i.v.). Low levallorphan doses induce an electrographic arousal (low voltage, fast waves in the sensorimotor cortex, acceleration of the synchronized 5 to 7 c/s group activity in the thalamus, rhinencephalon and parieto-occipital cortex) combined with increased alertness.

Morphine and levorphan depress or abolish the electrographic attention or arousal response to human presence or to stimulation of the midbrain reticular formation. Levallorphan increases this response at higher doses.

Morphine and levorphan increase the excitability of the thalamic intralaminary system. Levallorphan strongly decreases it at all doses.

Morphine enhances the activity of the rhinencephalon (hippocampus) and of its projections. Levallorphan has the opposite action, especially when low doses are given.

Our experiments bring pharmacological evidence of the existence of a functional interaction between the thalamic intralaminary system and the midbrain reticular formation (Moruzzi and Magoun, 1949). Morphine and levallorphan as typical antagonistic substances act in opposite ways on these two systems, involved in the organization of consciousness and pain. Thus morphine activates the thalamic intralaminary system, at doses which depress consciousness and pain, whereas levallorphan, at doses necessary to antagonize the morphine analgesia, activates the reticular formation at the midbrain level.

One of the main differences between analgesics and tranquillizers may be their different actions on the intralaminary thalamus and reticular formation. The recruiting activity of the intralaminary thalamus is enhanced by morphine and depressed by reserpine or serotonin; the midbrain reticular system on the contrary is depressed by morphine, but not markedly influenced by reserpine or serotonin.

Similarly the two groups of drugs have opposite actions on the rhinencephalon (hippocampus). This system is activated by morphine and depressed by levallorphan.

The mechanism of the antagonizing actions of levallorphan against morphine is discussed. This drug is relatively ineffective against other depressing agents, such as barbiturates, which also depress the respiration, because the topic action of the latter is different from that of the narcotics.