The role of morphine-3-glucuronide, morphine-6-glucuronide, and gender differences in morphine analgesia in rats and humans

Morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) are the two major pharmacologically active metabolites of morphine. The pharmacology of M3G and M6G is not yet completely understood. To further elucidate the effects of M3G and M6G, in vivo and in vitro studies were completed.; To study the effects of M3G and M6G on the function of opioid receptors, changes in cAMP were measured in SK-N-SH cells. It was concluded that inhibition of cAMP evoked by activation of opioid receptors and inhibitory G-proteins may play a role in the actions of M3G and M6G.; In Xenopus leavis oocytes transfected with human opioid receptors, potassium channel responses were recorded using a patch clamp technique. It was concluded that both M6G and M3G are opioid receptor agonists with different potencies and that the potency of morphine and M6G can be altered by selectively mutating amino acids on the μ opioid receptor.; To assess the contributions of M3G and sex differences to morphine analgesia, an in vivo study was conducted in male and female rats. The hot-plate was used as an algesiometric test. Multiple blood samples were collected from the jugular vein. Plasma concentrations of morphine and M3G were measured by HPLC with fluorescence detection. It was concluded, that sex and/or gonadal steroids contribute to differences observed in the M3G:morphine plasma ratio and these differences may be partially responsible for the male-female differences in morphine antinociception observed in rats.; The contributions of M3G and M6G to gender differences in morphine analgesia were investigated also young and elderly men and women. The cold pressor test was used to measure pain threshold, tolerance, and intensity. Concentrations of morphine, M3G, and M6G were measured simultaneously by HPLC and tandem mass spectrometry. Correlation analysis showed that the higher the plasma M3G:morphine ratio, the lower the post-morphine pain tolerance. The results suggest that the contributions of the glucuronides to morphine analgesia may vary among individuals in regard to ovarian steroids, gender, and/or age.; The results from the in vitro and in vivo projects demonstrate the importance of active glucuronides in the pain relieving effect of morphine.