Hypersensitivity of morphine-tolerant rabbits to the respiratory stimulant effect of a cholinergic agonist

The effect of morphine and oxotremorine, a centrally acting cholinergic agonist on the respiratory rate and arterial blood gases, was studied in rabbits given saline, increasing doses of morphine (5 mg/kg, 2 days; 10 mg/kg, 2 days; and 20 mg/kg, 3 days) injected at 12-hr intervals for 1 week. Care was taken to ensure that the chronically morphine-treated rabbits were neither under the influence of a previous dose of morphine nor in a phase of withdrawal when the response to test doses was measured. Tolerance to the respiratory depressant effect of morphine was demonstrated by the finding that a 5 times greater dose of morphine was needed to decrease respiration rate and raise arteriolar pCO₂ than that given to saline-treated rabbits. The respiratory stimulant effect of oxotremorine, as demonstrated by an increase in respiration rate and decrease in Pa(Co)₂, was significantly greater in morphine-tolerant rabbits. It is concluded that chronic opiate treatment can induce supersensitivity of the cholinergic systems subserving control of respiration.