Morphine-3-Glucuronide, Physiology and Behavior

Abstract

Morphine remains the gold standard painkiller available to date to relieve severe pain. Morphine metabolism leads to the production of two predominant metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). This metabolism involves uridine 5′-diphospho-glucuronosyltransferases (UGTs), which catalyze the addition of a glucuronide moiety onto the C3 or C6 position of morphine. Interestingly, M3G and M6G have been shown to be biologically active. On the one hand, M6G produces potent analgesia in rodents and humans. On the other hand, M3G provokes a state of strong excitation in rodents, characterized by thermal hyperalgesia and tactile allodynia. Its coadministration with morphine or M6G also reduces the resulting analgesia. Although these behavioral effects show quite consistency in rodents, M3G effects are much more debated in humans and the identity of the receptor(s) on which M3G acts remains unclear. Indeed, M3G has little affinity for mu opioid receptor (MOR) (on which morphine binds) and its effects are retained in the presence of naloxone or naltrexone, two non-selective MOR antagonists. Paradoxically, MOR seems to be essential to M3G effects. In contrast, several studies proposed that TLR4 could mediate M3G effects since this receptor also appears to be essential to M3G-induced hyperalgesia. This review summarizes M3G’s behavioral effects and potential targets in the central nervous system, as well as the mechanisms by which it might oppose analgesia.

High bioavailability, short half-life, and metabolism into hydromorphone-3-glucuronide following single intramuscular and intravenous administration of hydromorphone hydrochloride to great horned owls (Bubo virginianus)

“…In mammals, hydromorphone is metabolized primarily by conjugation with glucuronic acid to form the metabolite H3G in a similar manner to morphine that forms morphine-3-glucuronide (M3G), the main metabolite of morphine. 20 In the study reported here, H3G was detectable in all birds at 30 minutes following drug administration by both the IV and IM routes and had measurable plasma concentrations up to 12 hours postadministration, which was the last time point measured. The quantifiable concentrations of this metabolite suggest that hydromorphone in GHOWs may have a similar metabolic profile as mammals.…”

“…It is unknown if H3G has analgesic effects; however, the structural analog M3G has been associated with neuroexcitant signs in rats without analgesic effects. In contrast, the morphine metabolite morphine-6-glucuronide has been associated with analgesic effects, 20,42 but an analgesic analog metabolite has not been identified for hydromorphone. A study 41 investigating the neuroexcitant effects of H3G in rats revealed that it can induce dose-dependent-excitatory behaviors such as myoclonus, changes in body postures, and tonic-clonic seizures.…”

“…19 In mammals, hydromorphone is metabolized to form the metabolite hydromorphone-3-glucuronide (H3G). 20 Hydromorphone pharmacokinetics have been previously investigated in orange-winged Amazon parrots (Amazona amazonica), 21 cockatiels (Nymphicus hollandicus), 22 and American kestrels (Falco sparverius), 23 however, to our knowledge, the metabolite H3G has not been evaluated in any avian species to date.…”

Sex differences in neurotransmitter levels in different brain regions after acute and chronic morphine treatment in mice

“…We have recently shown that morphine antinociception and tolerance, as well as its metabolism in the brain, are influenced by sex [31]. In the brain, morphine is metabolized into its predominant metabolite M3G which is believed to oppose morphine effects ( i.e ., produces hyperalgesia) [32]. Although M3G mechanism of action remains unclear, several studies have suggested an alteration of neurotransmission as a consequence of M3G effects (for review, see Gabel 2022).…”

Does nonlinear blood-brain barrier transport matter for morphine dosing strategies?

“…M3G displays a relatively low affinity for opioid receptors and has no analgesic activity. In fact, an opposite effect, hyperalgesia, has been reported (Frölich et al, 2011; Gabel et al, 2022). M6G, however, is capable of eliciting profound analgesic activity, and has even been propose to as the main drive of the analgesic effects of morphine treatment (Klimas and Mikus, 2014; Murthy et al, 2002).…”