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

morphine impairs memorisation processes and reduces LTP at
hippocampal synapses (93). Moreover, another experiment in rats
showed that one-off exposure to high-dose morphine (10 mg/kg
administered intraperitoneally) impaired memorisation in a cross-
maze model. The effects of exogenous morphine on memorisation
are therefore as yet poorly understood and seem to depend on
both dosage and stage of development. In the light of all these
observations and because both endogenous morphine and µ receptors
are known to be present in the hippocampus, it could be that
endogenous morphine plays a role in controlling memorisation
functions.

Morphine, neurogenesis and the growth of nerve cells

In the brain of adult mammals, there are two sites of ongoing
neurogenesis, namely the sub-ventricular zone (SVZ) along the edge
of the lateral ventricle, and the sub-granular zone (SGZ) of the
hippocampal dentate gyrus. Many contradictory results have been
published on the effects of morphine on the multiplication of neuronal
progenitors in the SGZ, reflecting the complexity of the underlying
mechanisms [reviewed in (94)]. In rats and mice on long-term
morphine (10 mg/kg administered intraperitoneally), neurogenesis has
been observed to be decreased by a factor of over 30% in the SGZ (95,
96), whereas other experiments have shown that morphine stimulated
multiplication (97, 98). Moreover, in µ receptor knock-out mice, an
increase of over 50% was documented in the rate of survival of newly
formed neurones in the granular zone of the dentate gyrus four weeks
after the injection of bromodeoxyuridine [BrdU, a marker for
neurogenesis (99)]. Endogenous morphine in the hippocampus (78)
could therefore regulate the production and survival of neuronal
progenitors, thereby affecting synaptic plasticity in the hippocampus.
These data are supported by the results of clinical studies which point
to hippocampal plasticity problems in heroin addicts (100).

With respect to cell growth, in vitro studies have shown that
morphine has dose-dependent effects on the growth of neural
processes (axons and dendrites) in cell lines and primary neurones
in tissue culture: at high concentrations (10 mM-10 µM), morphine

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