Effects of modulating morphine metabolism on its pharmacological action in guinea pigs

Morphine is extensively metabolized to neurotoxic morphine-3-glucuronide (M3G) and opioid agonist morphine-6-glucuronide (M6G). Due to these different metabolic fates, interindividual variability and interactions with co-administered drugs may lead to differences in the analgesic effect. The aim of the study was to investigate the repercussions of an inducer (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) and an inhibitor (ranitidine) of glucuronidation in morphine metabolism and consequent analgesia, using guinea pigs as a suitable model.

Thirty male Dunkin-Hartley guinea pigs were divided in six groups: control, morphine, ranitidine, ranitidine + morphine, TCDD and TCDD + morphine. After previous exposure to TCDD and ranitidine, morphine effect was assessed by an increasing temperature hotplate (35–52.5 °C), during 60 min after morphine administration. Then, blood was collected and plasma levels of morphine and metabolites were quantified by liquid chromatography.

Animals treated with TCDD presented faster analgesic effect and 75% reached the cut-off temperature, comparing with only 25% in morphine group. Animals treated with ranitidine presented a significantly lower analgesic effect, compared with morphine group (p < 0.05). Moreover, significant differences between groups were found in M3G levels and M3G/morphine ratio (p < 0.001 and p < 0.0001), with TCDD animals presenting the highest values for M3G, M6G, M3G/morphine and M6G/morphine, and the lowest value for morphine. The opposite was observed in the animals treated with ranitidine.

Our results indicate that modulation of morphine metabolism may result in variations in metabolites concentrations, leading to different analgesic responses to morphine, in an animal model that may be used to understand and improve morphine effect in clinical practice.