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

Activating potassium channels at the same time as blocking
voltage-dependent calcium channels inhibits neurotransmitter
release so two typical effects of binding at µ receptors are, on the
one hand reduced GABA release by hippocampal interneurones (18),
and on the other reduced glutamate release by neurones in the
striatum (19).

In addition to these three mechanisms, it has been shown that
activation of µ receptors can affect other signalling pathways
specific to other cell-types (20, 21), e.g. in endothelial cells and some
types of immune cell (notably leukocytes). Thus, the stimulation
of µ receptors induces the generation and release of nitrogen oxide
(NO) via a PKC-dependent mechanism (1, 22, 23). Morphine’s
immunosuppressive activity seems to be dependent on µ receptor-
mediated induction of a cascade of MAP kinases in lymphocytes and
polymorphonuclear cells (24).

It has also been shown that GIRK (G-protein activated Inwardly
Rectifying K+ current) channels are involved in the analgesia induced
by the bolus injection of morphine, especially through its action at
the Periaqueductal gray matter (PAG): the drug inhibits GABAergic
interneurones thereby lifting the inhibition of PAG neurones which
are involved in descending control of nociception (25-27). Other
experiments have shown that opiate inhibition of neurones in the
dorsal layer of the spinal cord also involves GIRK channels. This
mechanism underlies the analgesic effect obtained by injecting µ
receptor agonists intrathecally (28, 29). Finally, recent work has
revealed the role played by GIRK channels in tolerance and addiction
when morphine is administered on a long-term basis (30, 31).

c) Morphine catabolism

Enzymes

Exogenous morphine is mainly inactivated (i.e. detoxified) in
the liver by a superfamily of enzymes referred to as the UDP-
glucuronosyltransferases [UGT (32)]. Different forms of UGT are
found in the gut and kidneys [reviewed in (33)] and recently, the
presence of UGT2B7 was found in the brain, suggesting that

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