3. Umbruch 4.4..2005 - Online Pot

226 F. Barth and M. Rinaldi-Carmona
[52]. In addition, cannabinoids also interact with known opioid reward pathways,
as indicated by the synergistic action of cannabinoid and opioid antagonists
on food intake [53, 54]. These results suggest that the central cannabinoid
system may act to amplify certain motivation indices and that blockade
of its interaction with the reward system may contribute to the effects of CB 1
antagonists on food intake.
Peripheral mechanisms and effects on metabolic processes
Recently, a third, purely peripheral, mechanism of action was also proposed by
several authors to explain some of the effects of SR-141716 on body weight. A
direct effect of SR-141716 on the activation of metabolic processes was proposed
by Ravinet-Trillou et al. [33]. This was supported by the fact that during
the course of a 5-week study using DIO mice the drug produced only a transient
effect on food intake, yet a sustained effect on body weight. Moreover,
SR-141716-treated mice had an accelerated weight loss versus control during
a 24-h fast and the weight loss was increased in SR-141716-treated mice compared
with pair-fed animals [28]. Chronic treatment with SR-141716 also
reduced the respiratory quotient of obese Zucker rats from 0.9 to 0.7, a change
consistent with an increase in fat oxidation [55] and it was shown that metabolic
factors contribute to the lean phenotype in adult mice with a disrupted
CB 1 gene (CB 1 –/– mice) [56]. A direct action of SR-141716 on adipocytes may
be responsible for this peripheral effect, as CB 1 mRNA was detected in mouse
and rat adipocytes [56, 57]. Interestingly, SR-141716 was shown to increase
adiponectin mRNA expression in adipose tissue of obese fa/fa rats and in cultured
mouse adipocytes. Adiponectin (Acrp 30) is a plasma protein exclusively
expressed and secreted by adipose tissue which has been shown to increase
fatty acid oxidation and improve insulin sensitivity and so reduce body weight.
This effect of SR-141716 was abolished in CB 1 -/- mice, indicating the involvement
of CB 1 receptor [57]. All these results clearly underline that cannabinoid
antagonists such as SR-141716 could exert a ‘peripheral’ metabolic action in
addition to their known ‘central’ effect on food intake.
Other recent studies demonstrated that sensory deafferentation which
destroyed the sensory terminals innervating the gut abolished both the hyperphagic
effects of cannabinoid agonists and the hypophagic effect of
SR-141716. These results suggest that CB 1 receptors, located in the gastrointestinal
tract, may also participate in the modulation of feeding induced by
cannabinoid agonists and antagonists [58].
Conclusion
Once considered as purely anecdotal, the effects of cannabinoids on appetite
are now the subject of intense interest in the scientific community. The natural