Control of spasticity in a multiple sclerosis model is mediated by CB1, not CB2, cannabinoid receptors

Background and Purpose: There is increasing evidence to suggest that cannabis can ameliorate muscle-spasticity in multiple sclerosis, as was objectively shown in experimental autoimmune encephalomyelitis models. The purpose of this study was to investigate further the involvement of CB(1) and CB(2) cannabinoid receptors in the control of experimental spasticity. Experimental approach: Spasticity was induced in wildtype and CB(1)-deficient mice following the development of relapsing, experimental autoimmune encephalomyelitis. Spastic-hindlimb stiffness was measured by the resistance to flexion against a strain gauge following the administration of CB(1) and CB(2) agonists. Key Results: As previously suggested, some CB(2)-selective agonists (RWJ400065) could inhibit spasticity. Importantly, however, the anti-spastic activity of RWJ400065 and the therapeutic effect of non-selective CB(1)/CB(2) agonists (R(+) WIN55,212-2 and CP55, 940) was lost in spastic, CB(1)-deficit mice. Conclusions and Implications: The CB(1) receptor controls spasticity and cross-reactivity to this receptor appears to account for the therapeutic action of some CB(2) agonists. As cannabinoid-induced psychoactivity is also mediated by the CB1 receptor, it will be difficult to truly dissociate the therapeutic effects from the well-known, adverse effects of cannabinoids when using cannabis as a medicine. The lack of knowledge on the true diversity of the cannabinoid system coupled with the lack of total specificity of current cannabinoid reagents makes interpretation of in vivo results difficult, if using a purely pharmacological approach. Gene knockout technology provides an important tool in target validation and indicates that the CB(1) receptor is the main cannabinoid target for an anti-spastic effect.