title: Control of spasticity in a multiple sclerosis model is mediated by CB1, not CB2, cannabinoid receptors.
abstract: OBJECTIVE
  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 CB1 and CB2)cannabinoid receptors in the control of experimental spasticity.
  
  
  METHODS
  Spasticity was induced in wildtype and CB1-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 CB1 and CB2 agonists.
  
  
  RESULTS
  As previously suggested, some CB2-selective agonists (RWJ400065) could inhibit spasticity. Importantly, however, the anti-spastic activity of RWJ400065 and the therapeutic effect of non-selective CB1/CB2 agonists (R(+)WIN55,212-2 and CP55, 940) was lost in spastic, CB1-deficit mice.
  
  
  CONCLUSIONS
  The CB1 receptor controls spasticity and cross-reactivity to this receptor appears to account for the therapeutic action of some CB2 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 CB1 receptor is the main cannabinoid target for an anti-spastic effect.
authors.affiliation: Department of Neuroinflammation, Institute of Neurology, University College London, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Pryce
authors.forename: D
authors.initials: D
authors.lastname: Baker
mesh_terms: D000818:Animals; D048588:Benzoxazines; D001831:Body Temperature / Q000187:drug effects; D003429:Cross Reactions; D003511:Cyclohexanols / Q000494:pharmacology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000150:complications / Q000188:drug therapy; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009103:Multiple Sclerosis / Q000150:complications / Q000188:drug therapy*; D009128:Muscle Spasticity / Q000188:drug therapy* / Q000209:etiology; D009281:Naphthalenes / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000502:physiology*
chemical_list: D048588:Benzoxazines; D003511:Cyclohexanols; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol