THE ACTION OF MORPHINE ON THE MAMMALIAN CIRCULATION

¹ From the Laboratory of Pharmacology, University of Pennsylvania

1. Intravenous injection of morphine causes a marked and primary fall in blood pressure in dogs and cats, unanesthetized, decerebrated, or anesthetized. Subcutaneous injection also causes a fall in pressure, but much larger doses are required. In rabbits, rats, and guinea pigs no fall in pressure occurs, even upon intravenous injection of relatively enormous doses.

2. Depression of the vasomotor center probably plays some part in this effect, but most of it is due to dilatation of cutaneous and muscular blood vessels by direct action upon their walls. The isolated heart is depressed by morphine, but the heart in situ is not significantly affected by doses sufficient to cause a marked fall in blood pressure. Central cardiac inhibition and respiratory depression play no part in the depressor effect of morphine injected intravenously.

3. Chronically poisoned tolerant dogs are highly resistant to the depressor effect of such injections, but chronically poisoned dogs that have not become tolerant have no such resistance. The circulatory response to intravascular injection of a small quantity of morphine therefore furnishes a ready means of testing for the presence or absence of tolerance to it, provided that morphine was the only drug of the group that has been given.

4. Upon repeated intravenous injections of morphine in normal dogs, the depressor effect diminishes progressively and soon disappears, blood pressure recovers, and even enormous quantities of morphine cease to have any depressor effect. This is due to the rapid appearance of resistance to the vasodilator action, comparable with that displayed by the chronically poisoned tolerant animal. Similar results can be obtained by subcutaneous injection of a fairly large dose of morphine. For this phenomenon the term "acute tolerance" is proposed.

5. Evidence is presented that the property of rapidly becoming resistant to the depressant effects of morphine upon exposure to high concentrations of it is not peculiar to the blood vessels, but is shared by the vasomotor and respiratory centers. The following paper contains evidence that the same is true of the cerebrum as a whole.

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