Comparative measurement of spinal CSF microdialysate concentrations and concomitant antinociception of morphine and morphine-6β-glucuronide in rats

Morphine-6β-glucuronide (M6G) is well known as a potent active metabolite in humans. To clarify concentration–antinociceptive effect relationships for morphine and M6G, we evaluated comparatively the pharmacokinetics and antinociceptive effects of morphine and M6G. The spinal CSF concentration and antinociception were simultaneously measured by using the combination of a microdialysis method and the formalin test in conscious rats after the s.c. administration of morphine (0.3–3 mg/kg) and M6G (0.1–3 mg/kg). The plasma concentration of M6G after s.c. administration was higher than that of morphine, as shown by the 2.1 times greater value of area under the concentration–time curve (AUCplasma). The spinal CSF concentrations of morphine and M6G increased dose-dependently. The AUCCSF of M6G was 1.6–1.8 times higher than that of morphine at each dose. Administration of morphine and M6G dose-dependently suppressed the flinching behavior induced by formalin injection. The ED50 values for M6G were 3 times lower than those of morphine, although the spinal CSF concentration versus antinociceptive effect curves of morphine and M6G were very similar, with similar EC50 values. These results suggest that the antinociceptive potencies of morphine and M6G, evaluated by simultaneous measurements of spinal CSF drug concentration and antinociception, are equivalent. Simultaneous measurement of spinal CSF concentration and antinociception by using microdialysis should be useful for elucidating the relationship between pharmacokinetics and pharmacodynamics of various opioids.