Ventilatory Effects of Fourth Cerebroventricular Infusions of Morphine-6− or Morphine-3-Glucuronide in the Awake Dog

The ventilatory effects of morphine-6-glucuronide (M-6-G) and morphine-3-glucuronide (M-3-G) were evaluated in awake dogs (n = 10). A fourth ventricle to cisterna magna perfusion (VCP) system was used for drug administration. This permitted a direct comparison of the dose/ventilatory response characteristics of these morphine metabolites to each other and to morphine and obviated the need to consider the blood-brain barrier delay that would complicate analysis of systemic dose versus ventilatory response relationships among these drugs. The dose/response pattern for morphine was taken from an earlier study in unanesthetized dogs where the identical mode of drug delivery as in the present report was employed. Morphine-3-glucuronide caused, if anything, a ventilatory stimulation (decreased PaCO2 and increased CO2 responsiveness) at the highest infusate concentration studied (50 micrograms/ml) and no significant ventilatory effects at infusate concentrations at or below 10 micrograms/ml. On the other hand, M-6-G produced a profound dose-dependent ventilatory depression. Significant increases in PaCO2 and diminution of CO2 responsiveness were observed even at the lowest infusate concentration evaluated (0.1 microgram/ml). When compared to morphine, M-6-G was found to be about five to ten times more potent as a ventilatory depressant drug. These results imply that M-6-G may play a significant role in the ventilatory depression accompanying systemic morphine administration.