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YANNICK GOUMON Y COLS. AN. R. ACAD. NAC. FARM.

in the thalamus, the putamen, the black substance, the cortex, the
ventral tegmental zone, the nucleus accumbens and the amygdala
(8, 9). In the periphery, µ receptors are expressed on endothelial
cells (10, 11) and cells of the immune system (12), among others.

Pharmacological experiments and ligand binding studies have
shown that there are several different isoforms of the µ receptor:

— µ1 is mainly expressed in the CNS and has a high affinity for
morphine -it is this form that mediates the drug’s analgesic
activity;

— µ2 is expressed in the CNS, the respiratory system and the gut,
and mediates most of the drug’s side effects (3);

— µ3 is found on human monocytes, granulocytes and endothe-
lial cells.

However, whether or not these three different isoforms really
exist is now controversial because all µ receptors are encoded by a
single gene, Opioid Receptor Mu 1 (OPRM1) in humans and Oprm1
in mice, and the different forms are generated by alternative splicing.
Currently, 28 different variants have been described in mice (13, 14),
and ten different forms have been characterised in humans (15).
This classification system is continually changing and it is more
than likely that other variants will be identified.

Signal transduction mechanisms of the µ receptors

The activation of Gi/Go proteins inhibits cellular activity by
means of three main mechanisms [reviewed in (5)]:

— by inhibiting adenylate cyclase activity leading to a reduction
in cAMP generation. However, it is important to remember
that repeated exposure to morphine will lead to enhanced
adenylate cyclase activity, a phenomenon which seems to
contribute to the addictiveness of opiates (16);

— by opening potassium channels which leads to increased K+
flux and hyperpolarisation of the cell (17);

— by blocking voltage-dependent calcium channels and decrea-
sing permeability to Ca2+ (17).

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