SMALL PART OF CANNABIS PUZZLE SOLVED BY ANIMAL STUDIES

Researchers studying the cannabinoid signalling system may have identified
a new target for the treatment of pain. Benjamin Cravatt (Scripps Research
Institute, La Jolla, CA, USA) and colleagues report that fatty acid amide
hydrolase (FAAH) is a key in-vivo regulator of anandamide, an endogenous
cannabinoid receptor ligand. "We have many more experiments to do",
cautions Cravatt, "but our results indicate that it might be possible to
develop FAAH inhibitors to prime the endogenous cannabinoid system so that
it responds selectively in neural pathways that are stimulated by pain."

Anecdotal evidence indicates that cannabis can control chronic pain in
conditions such as multiple sclerosis. But because cannabis use is illegal
in many parts of the world, discussion of medical marijuana is
controversial. A better understanding of the endogenous cannabinoid
signalling pathway may indicate targets for new pain-killing drugs and so
circumvent the debate on medical marijuana, say some researchers.

Cravatt and co-workers are studying anandamide, a fatty acid amide that
behaves like a cannabinoid in vitro but has weak, transient in-vivo
behavioural effects. "We postulated that rapid degradation of anandamide in
vivo could explain its lack of effect compared with tetrahydrocannabinol
(THC), marijuana's active component", says Cravatt. In 1996, the team
cloned FAAH, an enzyme that degrades anandamide and they have now bred mice
lacking the FAAH gene. These mice "cannot effectively degrade anandamide so
they have 15-fold higher endogenous levels than wild-type mice", adds
Cravatt. Nevertheless, the mice seem normal until injected with anandamide.
Then, they show behaviour similar to that seen with THC. The knockout mice,
even without anandamide treatment, have reduced pain sensitivity that can
be reversed by a cannabinoid receptor antagonist, indicating that increased
endogenous anandamide in FAAH knockout mice affects their pain pathways
(Proc Natl Acad Sci 2001; 98: 9371-76). "If in-vivo FAAH inhibitors can be
developed, they may provide a selective way to use the cannabinoid
signalling system for chronic pain relief", suggests Cravatt.

"This is another interesting part of the puzzle", comments William Notcutt
(James Paget Hospital, Great Yarmouth, UK). "However, the philosopher's
stone of something that mimics the good effects of cannabis without having
the bad effects may be an impossible goal. We've tried that approach
unsucessfully with morphine." Instead, says Notcutt, more effort should go
into clinical testing of defined cannabis extracts. "Chronic pain is a
complex phenomenon and there is a huge amount of work waiting to be done
with existing agents", he concludes. Jane Bradbury