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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 271; no. 1; pp. 118 - 124
• Main Authors: Murphey, L J, Olsen, G D
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.10.1994
• Subjects: Animals; Animals, Newborn; Brain - metabolism; Diffusion; Guinea Pigs; Morphine - pharmacology; Morphine Derivatives - pharmacokinetics; Respiration - drug effects; Solubility
• ISSN: 0022-3565; 1521-0103

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.