Diffusion of morphine-6-beta-D-glucuronide into the neonatal guinea pig brain during drug-induced respiratory depression

LJ Murphey and GD Olsen

Department of Pharmacology, School of Medicine, Oregon Health Sciences University, Portland.

Morphine-6-beta-D-glucuronide (M6G) is an active metabolite of morphine. In a previous study, M6G depressed respiration in the neonatal guinea pig, becoming more potent with aging, a finding that is confirmed in the current study. After s.c. injection, M6G is absorbed into plasma, crosses the blood-brain barrier and is present in the central nervous system at the time of maximal M6G-induced ventilatory depression. No hydrolysis of M6G to morphine is detected in either plasma or brain tissue by high-performance liquid chromatography. About 30% more M6G is in plasma in 3-day-old than in 7-day-old pups after drug administration (P < .05). Mean brain concentrations of M6G are 12% higher on day 3 than day 7, but the difference is not statistically significant. Brain-to-plasma ratios of M6G do not differ after 5 or 15 mg/kg of M6G or with age (mean ratio = 0.037). Brain drug concentration is a linear function of plasma drug levels (r2 = 0.84), suggesting M6G crosses the blood brain barrier by diffusion. Differential systemic absorption or central nervous system distribution of M6G cannot explain enhanced respiratory depression with aging. Morphine-3-beta-D- glucuronide (M3G) also crossed the blood-brain barrier, but is less permeable than M6G (mean brain-to-plasma ratio = 0.022). Contrary to reports in the literature, M3G at a dose of 75 mg/kg, does not stimulate respiration in this study. Morphine administration to neonatal guinea pigs produces measurable plasma and brain levels of M6G and M3G.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 271, Issue 1, pp. 118-124, 10/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics