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 - --- MAP posted-by: Larry Stevens