SAN DIEGO - At first glance, the potential uses of endocannabinoid receptor manipulation look a bit like Every Flavor Beans, referenced in the Harry Potter books. At this year's annual meeting of the Society for Neuroscience, held here last week, research was presented that probed the role of endocannabinoids in such diverse subfields as amyotrophic lateral sclerosis, appetite regulation, convulsions, drug abuse, neural plasticity, pain, Parkinson's disease and traumatic brain injury - and that list is not comprehensive.

Add to that the fact that both agonists and antagonists are being described as beneficial - sometimes in the same poster session.

As receptor families go, the endocannabinoid one is small - as of now it consists of just two members: CB1 and CB2. CB1 receptors are found predominantly in the nervous system and are responsible for the psychoactive and behavioral effects of marijuana. They are located mainly presynaptically. CB2 receptors are associated mainly with inflammatory and immune cells.

In the commercial arena, Sanofi-Synthelabo SA (now Sanofi-Aventis Group) is furthest along in developing endocannabinoid receptor antagonists; its Acomplia (rimonabant), a CB1 receptor antagonist, recently concluded Phase III trials for obesity and smoking cessation. Presenting considerably earlier-stage data at Neuroscience was Israeli biotech Pharmos Inc. Pharmos scientists presented two posters investigating the effects of the CB2 receptor agonist PRS-211,375 on neuropathic pain and multiple sclerosis, respectively.

In their neuropathic pain work, the scientists tested two pain models: inflammation-induced pain, and direct nerve damage caused by the chemotherapy agent Taxol (paclitaxel).

Neuropathic pain is a frequent side effect of Taxol, which damages peripheral nerve endings. Testing the ability of PRS-211,375 to alleviate that pain in rats, the researchers found dose-dependent analgesic effects.

In an inflammation-induced pain model in which neuropathic pain is induced in one leg only, the scientists found that their compound provided pain relief that was equal to or better than that achieved by morphine. Furthermore, "morphine affects the healthy leg, suggesting it works through the central nervous system," Sigal Meilin, senior scientist at Pharmos, told BioWorld Today. In contrast, administration of PRS-211,375 had no effect on the control leg, suggesting it is active locally by affecting either CB2 or peripheral CB1 receptors. Pharmos scientists believe it is likely acting on CB2 receptors, though Meilin cautioned that that has not been conclusively demonstrated.

In their multiple sclerosis investigations, the scientists tested the effects of PRS-211,375 in animal models of three different types of multiple sclerosis: acute, remitting relapsing, and chronic progressive. In all cases, orally administered PRS-211,375 was effective in reducing the severity of symptoms and inhibiting progression of the disease. Meilin noted that one particular advantage of PRS-211,375 appears to be its effectiveness when given after disease induction rather than prophylactically.

Pharmos also has another CB2 receptor agonist in clinical trials for traumatic brain injury and cardiovascular indications. (See BioWorld Today, Aug. 24, 2004.)

Both pain and neurodegenerative disease also are the subjects of academic investigations into the effects of endocannabinoid receptors. In the field of endocannabinoid pain research, Pierre Beaulieu from the University of Montreal and his colleagues reported on their research into the interactions between endocannabinoids and nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen and rofecoxib.

Since NSAIDs inhibit the enzyme that normally degrades the endogenous endocannabinoid ligand anandamide, Beaulieu's group was interested in the interactions between both types of analgesics. In an animal model of inflammation-mediated pain, anandamide led to pain relief and had additive effects with both ibuprofen and rofecoxib.

When the researchers tried to reverse the effects of those drugs by using cannabinoid receptor antagonists, a CB2 receptor antagonist reversed the effects of anandimide alone. However, a CB1 receptor antagonist reversed the effects of anandimide and ibuprofen in combination. In a press briefing, Beaulieu acknowledged that this was "surprising," but declined to speculate on possible mechanisms.

Mary Abood and her colleagues from the California Pacific Medical Center are investigating the possible benefits of THC (the psychoactive ingredient in marijuana, endocannabinoid's most famous ligand) in an animal model of amyotrophic lateral sclerosis, or Lou Gehrig's disease.

"In ALS, motor neurons are damaged through both excitotoxicity and oxidative stress, and endocannabinoids affect both," she said at a press briefing. In a mouse model of ALS, treatment with THC both improved motor performance and extended life span.

Andrea Giuffrida's group at the University of Texas at San Antonio is testing the uses of endocannabinoid receptor ligands in a mouse model of Parkinson's disease. When mice were pre-treated with either a receptor agonist or antagonist prior to injection of MPTP, a substance which has metabolites that kill dopaminergic neurons in the substantia nigra (the types of neurons that degenerate in Parkinson's disease), surprisingly, both substances had a neuroprotective effect. The researchers investigated the mechanism of action of that effect and found that both substances were interfering with the uptake of MPP+ metabolites into cells - an interesting phenomenon, but one of comparatively little clinical value, since few people other than regular recreational marijuana users are likely to prophylactically activate their endocannabinoid receptors.

When the researchers waited until after the toxin had been taken up by the cells, only the agonist was effective in preventing cell loss, while the antagonist had little effect. However, both agonists and antagonists were effective in preventing MPTP-induced hyperactivity.

Those results suggest that much remains to be learned about the mechanisms underlying the effects of endocannabinoid receptor activation.

Check back at Neuroscience 2005.