Comparative ventilatory effects of intravenous versus fourth cerebroventricular infusions of morphine sulfate in the unanesthetized dog

The ventilatory pharmacodynamics of morphine sulfate (MS) in the awake dog (n = 14) were investigated. Two routes of MS administration were employed: 1) 4 h continuous intravenous (iv) infusion (1 mg.kg-1 loading dose, 10 micrograms.kg-1.min-1 thereafter); and 2) fourth ventricle to cisterna magna perfusion (VCP) at increasing infusate morphine concentrations (0.1-100 micrograms.ml-1). The former was associated with a constant plasma and cisternal CSF (and presumably tissue) free morphine concentration. The latter produced, over 1 h at a constant infusate morphine delivery, a cisternal CSF free morphine concentration that leveled off by 30 min, little or no distribution of drug beyond superficial dorsal and superficial ventral brainstem tissue, and no detectable levels of morphine in plasma. When comparing the two routes of administration, ventilatory depression for a given cisternal free morphine level in the iv infusion studies was of a much greater magnitude than that seen in VCP experiments. Differences in the ventilatory patterns were also noted. Thus, iv delivery produced a decrease in tidal volume (VT) and no change or reduced respiratory frequency (f) with prolonged exposure. VCP delivery was also associated with reduction in VT but produced significant increases in f. An apparent maximal ventilatory depression with 1 h VCP administration was observed at morphine infusate levels of greater than 10 micrograms.ml-1, with higher infusate concentrations and extension of the perfusion period to 3 h producing no significant additional changes. Finally, VCP delivery of the mu-antagonist nalbuphine could only partially reverse the ventilatory depression accompanying iv morphine administration. These findings suggest that the ventilatory depression associated with iv morphine is a result of interactions with brain u-opiate receptors in superficial brainstem tissue and in deep brainstem and/or suprapontine tissue as well.