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VOL. 75 (3), 389-418, 2009 CENTRAL AND PERIPHERAL ENDOGENOUS MORPHINE

In humans, most M6G and M3G formation is catalysed by
UGT2B7, although UGT1A1 and 1A8 have been described as making a
minor contribution to M6G (38), while UGT1A3, 1A6, 1A9 and 1A10
can only catalyse the formation of M3G (34). Most UGT enzymes
are mainly expressed in the liver but some are found elsewhere,
e.g. UGT1A6 and UGT2B7 are expressed in the brains of rats and
humans (39), UGT1A6 is also expressed by rat neurones and astrocytes
in primary tissue culture (40), and UGT1A6 has been detected by in
situ hybridisation in pyramidal hippocampal neurones and Purkinje
cells in the rat cerebellum (41).

In humans, M3G —the major glucuronide product of exogenous
morphine— has zero affinity for opiate receptors and no analgesic
activity (32). M6G —which accounts for 10% of the morphine
breakdown products in the liver— can bind the µ receptor and has
been reported as being 1-600 times more active as an analgesic than
morphine itself, the variability depending on the model studied
(notably species) and the route of administration [intraventricular,
intravenous, etc.; reviewed in (2, 32 42)]. As well as these two
glucuronides, smaller amounts of other metabolites are also formed
and found in the urine, including morphine 3,6-diglucuronide,
normorphine, normorphine-6-glucuronide and morphine-3-sulphate,
with no or little analgesic activity (43, 44).

Before morphine or M6G can have any effect in the central
nervous system, they have to cross the blood-brain barrier (BBB).
M6G has been reported as crossing this barrier 32-57 less efficiently
than morphine (45) and its analgesic effects are mainly obtained
by intrathecal and intraventricular injection. Studies on the efficacy
of M6G in humans have yielded inconsistent results. One study
suggested that intrathecal M6G is 4-5 times more effective against
postoperative pain (46) while a number of studies have indicated
that very high doses of intravenous M6G are required for effective
analgesia [reviewed in (3, 32)]. Because of its strongly hydrophilic
nature, M6G does not cross the BBB efficiently and very high
intravenous doses (of the order of 0.3 mg/kg) are necessary to reach
a high enough M6G concentration in the brain for effective analgesia.
In contrast to morphine, M6G analgesia seems to last longer [6-8
hours compared with just 2-4 hours (47)] and it induces fewer side
effects, notably less vomiting and respiratory depression [reviewed

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