CB2 receptor agonists with anagesic activity

In the “Focus on CNS disease” section of this edition of TherapeuticAdvances we describe the development of HSV viral vector systems for the transduction of GNDF express into DRG cells in order to treat neuropathic pain. As described in that section approximately 9% of the US population suffers from moderate to severe non-cancer-related pain, a figure that includes 40-70 million individuals with chronic pain. This condition precipitates other serious pathologies such as depression and is associated with an estimated pharmaceuticals market of US$18.7 billion worldwide.

In their recent PNAS paper Ibrahim et al describe the use of CB2 agonists as a new approach to the treatment of pain, in particular neuropathic pain. This hyperalgesic condition is defined as pain caused by primary lesion or dysfunction in the nervous system and is associated with a variety of etiologies including trauma, infection, diabetes, immune deficiencies, ischemic disorders, and toxic neuropathies. Aproximately 26 million patients are affected worldwide and the lifestyle of this cohort can be severely impeded, a problem compounded by the lack of efficacy and frequent incidence of side effects associated with current treatment options.

Cannabinoids and their derivatives exert their effects via "central" CB1 receptors, mostly expressed in brain and responsible for cannabinoid psychoactivity, and "peripheral" CB2 receptors, mostly expressed in the immune system and unrelated to cannabinoid psychoactivity. In their publication, Ibrahim et al demonstrate that the CB2 selective agonist, AM1241, has analgesic activity. AM1241 is an aminoalkylindole analog, which has nanomolar affinity for the CB2 receptor. This molecule is selective binding to the CB1 receptor with an affinity of 280nM. Using a spinal nerve ligation model of neuropathic pain AM1241 was shown to dose-dependently inhibit tactile and thermal hypersensitivity in rats through its activation of the CB2 receptor. Since CB2 receptors do not appear to be expressed in the CNS this effect is likely to be mediated via a peripheral mode of action which, the authors propose, may result from modulation of the neuroimmune axis. Since AM1241 does not produce catalepsy, hypothermia, inhibition of spontaneous locomotor activity, or inhibition of performance on the rotarod apparatus this approach to the treatment of neuropathic pain may represent a strategy that avoids the side-effects that limit the therapeutic benefit of other CNS active molecules. Furthermore CB2 agonists may also be of benefit to inflammatory and nociceptive pain and perhaps more importantly since many patients with chronic pain suffer hyperalgesia with mixed components, CB2 agonists may offer a useful approach to these particularly challenging clinical states

Entry date Wednesday, September 17, 2003

Adapted from Ibrahim et al, Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10529-33. Epub 2003 Aug 13