Cannabinoids

The Biosynthesis, Fate and Pharmacological Properties of Endocannabinoids 169

5

New Drugs from the Endocannabinoid System

5.1

Regulation of Endocannabinoid Levels Under Pathological Conditions

Although we now know that the effects of endocannabinoids and exogenously
administered THC can be both qualitatively and quantitatively different, the fact
that the symptoms of many ailments have been reported to be alleviated by THC
andCannabisprovided the rationale to test whether pathological alterations of en-
docannabinoid signalling can be causative of pathological states, or of their signs.
There is now increasing evidence that endocannabinoid levels undergo significant
changesinseveralanimalmodelsofbothacuteandchronicdisorders.Inparticular,
they appear to be transiently elevated in specific brain areas during several patho-
logical conditions of the CNS, i.e. following insults or stressful stimuli, such as:

• Glutamate excitotoxicity, in the hippocampus (Marsicano et al. 2003)


• Food deprivation, in the hypothalamus and limbic forebrain (Kirkham et al.
  2002)


• Exposure to an aversive memory, in the basolateral amygdala (Marsicano et al.
  2002)


• Administration of a painful stimulus, in the periaqueductal grey (Walker et al.
  1999)

In these cases, endocannabinoid signalling is enhanced to minimize the impact
of the insult or of the stressful stimulus, respectively by:

• Protecting neurons from damage, via feed-back inhibition of glutamatergic
  neuron activity (Marsicano et al. 2003)


• Reinforcing appetite, via inhibition of anorexic signals (Kirkham et al. 2002; Di
  Marzo et al. 2001c; Cota et al. 2003)

– Suppressing aversive memories, via inhibition ofγ-aminobutyric acid (GABA)-

ergic signalling (Marsicano et al. 2002)

• Producing central analgesia, by suppressing the activity of nociceptive circuits
  (Walker et al. 1999)

Findings that CB 1 receptors appear to contribute significantly to protection
from stroke in animals (Parmentier-Batteur et al. 2002), and that 2-AG is protective
in a model of head trauma (Panikashvili et al. 2001), support the hypothesis that
endocannabinoidshaveaneuroprotectiverole.Infact,endocannabinoidsignalling
is also elevated in animal models of neurodegenerative diseases, such as:

• In reserpine- or 6-hydroxy-dopamine-treated rats (two models of Parkinson’s
  disease) at the level of the basal ganglia (Di Marzo et al. 2000b; Maccarrone et
  al. 2003c)