The role of metabolites in morphine analgesic effects

Morphine is metabolized into two main metabolites, morphine-3-glucuronide and morphine-6-glucuronide. Morphine-6-glucuronide is a potent analgesic that is responsible for up to 97% of the analgesic effect. Morphine-3-glucuronide does not bind to opioid receptors and is devoid of any analgesic effect. However, it activates the Toll-like 4 receptors initiating neurogenic inflammation in the central nervous system. This, in turn, is responsible for anti–analgesic and hyperalgesic effects. There are a number of strategies on how to inhibit this pronociceptive effect and finally improve morphine analgesia