Pubdate: Sat, 28 Jul 2001
Source: Lancet, The (UK)
Copyright: 2001 The Lancet Ltd
Contact:  http://www.thelancet.com/
Details: http://www.mapinc.org/media/231
Author: Jane Bradbury

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
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MAP posted-by: Larry Stevens