Morphine-6-glucuronide

Morphine-6-glucuronide (M6G) is a major active metabolite of morphine, and as such is the molecule responsible for much of the pain-relieving effects of morphine (and thus heroin). M6G is formed from morphine by the enzyme UDP-Glucuronosyltransferase-2B7 (UGT2B7). M6G can accumulate to toxic levels in kidney failure.

The μ-opioid receptor subtype 3 appears to be activated (agonized) by morphine-6β-glucuronide but not morphine itself. This finding is also true of certain heroin metabolites (6-MAM) but not morphine proper.

History of discovery
This analgesic activity of M6G (in animals) was first noted by Yoshimura.

Subsequent work at St Bartholomew's Hospital, London in the 1980s, using a sensitive and specific HPLC assay, accurately defined for the first time the metabolism of morphine, and the abundance of this metabolite (along with morphine-3-glucuronide and morphine-3,6-diglucuronide, both considered inactive metabolites).

It was postulated that renal impairment would result in accumulation of the renally-excreted active agent M6G, leading to potentially fatal toxicity such as respiratory depression. The frequent use of morphine in critically ill patients, and the common occurrence of renal failure in this group implied that M6G accumulation could be a common, but previously unanticipated problem. The first studies demonstrated massive levels of M6G in 3 patients with renal failure, which resolved as kidney function returned. Accumulation of M3G and M6G also decrease with return of renal function after renal transplantation.

A key step in defining the importance of M6G in man came in 1992 when the substance was artificially synthesised and administered to patients with pain, the majority of whom described pain relief.