LOW PERMEABILITY THROUGH THE BLOOD-BRAIN BARRIER OF MORPHINE GLUCURONIDES.

The glucuronide conjugates of morphine have been claimed to exert significant neuropharmacological effects. Morphine-6-glucuronide (M6G) may be a potent opioid agonist in vivo, and morphine-3-glucuronide (M3G) may act as a weak opioid antagonist. The present study addressed the permeability of the blood-brain barrier (BBB) for these metabolites compared to morphine. Tracers were prepared by enzymatic glucuronidation of U-methyl-$^3$H]-morphine. Brain uptake in rats was measured by the internal carotid artery perfusion technique and after i.v. bolus injections. In the perfusion experiments morphine showed a permeability-surface area product (PS) of 3.52${\pm}$0.61 ${\mu}$L min$\^$-1/ g$\^$-1/ Uptake seems to be mediated by passive diffusion and was not saturable by 100 ${\mu}$M morphine in the perfusate. The BBB permeability of [$^3$H]-M3G and [$^3$H]-M6G was too low to be quantified after 5 min of perfusion. Brain uptake of [$^3$H]-M3G and [$^3$H]-M6G 60 min after i.v. bolus injection reached 0.0060${\pm}$0.0003 and 0.0030${\pm}$0.0005% injected dose per g, respectively. From these brain concentrations and from the corresponding plasma concentration - time curves, BBB PS values of 0.14${\pm}$ 0.02 ${\mu}$L min$\^$-1/g$\^$-1/ and 0.11 ${\pm}$ 0.01 ${\mu}$L min$\^$-1/g$\^$-1/, respectively, were calculated. The ratio of BBB PS values is complementary to the analgesic potencies of morphine and M6G after different routes of administration. The low PS of MSG explains, why it is approximate]y equipotent to morphine after systemic injection, although it is about 2 orders of magnitude more potent than morphine after administration directly into the central nervous system.