HIGH HOPES FOR CANNABINOID ANALGESIA

Several decades of irrational prejudice may have hampered clinical research
on cannabis as a medicine, but work on the pharmacology of its active
ingredients has been making steady progress. Just as the body has a natural
counterpart to the opiate drugs, so too it makes its own endogenous
cannabinoids. These act through receptors, of which two variants--CB1 and
CB2--have been definitely identified and at least one other is suspected.
The CB1 receptors are located only in the brain; their CB2 counterparts are
found peripherally, and especially on the cells of the immune system.
Cannabinoid receptors are present not just in vertebrates but also in
molluscs, leeches, and other invertebrate groups that have been
evolutionarily separate for 500 million years. The fact that natural
selection has for so long conserved these receptors is an indication of
their physiological importance.

Anandamide, the first natural cannabinoid to be isolated, came to light in
1992. Its precise role, and those of the other cannabinoids that have since
been identified, remains uncertain; but evidence exists that all play a
part in memory, appetite, the control of movement, and, especially, the
modulation of pain.1 With respect to the last of these, the sites of
cannabinoid action in the central nervous system are confined to specific
areas, most of which--the dorsal horn of the spinal cord, for example2
3--are involved in processing pain signals. Clear parallels exist between
cannabinoid and opiod receptors, and evidence is accumulating that the two
systems sometimes interact,4 and may operate synergistically. One unproved
but intriguing idea is that endocannabinoids may set the "analgesic tone"
of the body, with the level of their production acting as a kind of pain
thermostat.

The perception of pain is controlled by neurotransmitter systems within the
central nervous system, but peripheral tissues also have mechanisms for
relieving and preventing pain. Cannabinoids may therefore have two distinct
roles in relation to pain. The evidence comes from animal experiments
showing that cannabinoids lower the response of pain neurones in the spinal
cord and also in parts of the thalamus in the brain. The possibility that
cannabinoid receptor subtypes act synergistically hints at a potentially
valuable strategy: the development of a new class of analgesic drug
comprising a mixture of synthetic CB1 and CB2 agonists. Alternatively,
devising agents to slow the breakdown of natural cannabinoids might
potentiate their analgesic effects.5

The brain has many more CB1 than opioid receptors, and interest in the
therapeutic potential of cannabinoids has prompted the development of
several synthetic variants, of which dronabinol is one.1 Many of these
compounds bind to both CB1 and CB2 receptors, but differences between the
two suggest that it should be possible to design drugs that would attach to
only one of them. This might offer a means of producing more selective
biological actions, including analgesia without some of the psychotropic
effects that might disturb people whose wish was to be pain-free but not
"high."

A review by the US Institute of Medicine has commented on how little we
know about cannabinoids in comparison with opiates.2 A comparison between
the history of research into the two groups, the review added, "suggests
good reason for optimism about the future of cannabinoid drug development."

REFERENCES

Svendsen KB, Jensen TS, Bach FW. Does the cannabinoid dronabinol
reduce central pain in multiple sclerosis? Randomised double blind
placebo controlled crossover trial. BMJ 2004;329: 253-7.

Joy JE, Watson SJ, Besnon JA, eds. Marijuana and medicine. Washington,
DC: National Academy Press, 1999.

Farquhar-Smith WP, Egertova M, Bradbury EJ, McMahon SB, Rice ASC,
Elphick MR. Cannabinoid CB(1) receptor expression in rat spinal cord.
Mol Cell Neurosci 2000;15: 510-21.

Tanda G, Goldberg SR. Cannabinoids: reward, dependence, and underlying
neurochemical mechanisms-a review of recent preclinical data.
Psychopharmacology 2003;169: 115-34.

Walker JM, Huang SM, Strangman NM, Tsou K, Sanudo-Pena MC. Pain
modulation by release of the endogenous cannabinoid anandamide. Proc
Natl Acad Sci 1999;96: 12198-203.