Antagonism of the cardiovascular and respiratory depressant effects of morphine in the conscious rabbit by physostigmine

The influence of physostigmine was studied on the effect of morphine on the cardiovascular and respiratory systems in conscious rabbits. Morphine (4 mg/kg i.v.) caused analgesia, bradycardia, hypotension and respiratory depression, as indicated by a fall in respiratory rate of 50%, a rise in blood Pa(CO₂) from 25.1 to 37.2 mm Hg and a fall in pH from 7.40 to 7.24. These effects lasted 2 to 3 hr and were completely antagonized by naloxone. Physostigmine (2.5 or 5 μg/kg/min) given by constant i.v. infusion did not significantly alter blood pressure or heart rate, but decreased blood Pa(CO₂) from 25.1 to 19 mm Hg and increased pH from 7.40 to 7.46. Pretreatment of rabbits with physostigmine (5 μg/kg/min) completely prevented both the fall in blood pressure and blood pH and the rise in Pa(CO₂) induced by morphine (4 mg/kg) and also significantly reduced both the intensity and duration of bradycardia. Analgesic activity of morphine remained unimpaired by physostigmine. Neostigmine (2.5 μg/kg/min) potentiated the bradycardia induced by morphine and did not antagonize its hypotensive and respiratory depressant effects. The results support the hypothesis that the respiratory and cardiovascular depressant effects of morphine, but not the analgesia, result from an inhibition of acetylcholine release from neurons in the central nervous system.