title: Control of experimental spasticity by targeting the degradation of endocannabinoids using selective fatty acid amide hydrolase inhibitors.
abstract: BACKGROUND
  It has been previously shown that CB1 cannabinoid receptor agonism using cannabis extracts alleviates spasticity in both a mouse experimental autoimmune encephalomyelitis (EAE) model and multiple sclerosis (MS) in humans. However, this action can be associated with dose-limiting side effects.
  
  
  OBJECTIVE
  We hypothesised that blockade of anandamide (endocannabinoid) degradation would inhibit spasticity, whilst avoiding overt cannabimimetic effects.
  
  
  METHODS
  Spasticity eventually developed following the induction of EAE in either wild-type or congenic fatty acid amide hydrolase (FAAH)-deficient Biozzi ABH mice. These animals were treated with a variety of different FAAH inhibitors and the effect on the degree of limb stiffness was assessed using a strain gauge.
  
  
  RESULTS
  Control of spasticity was achieved using FAAH inhibitors CAY100400, CAY100402 and URB597, which was sustained following repeated administrations. Therapeutic activity occurred in the absence of overt cannabimimetic effects. Importantly, the therapeutic value of the target could be definitively validated as the treatment activity was lost in FAAH-deficient mice. Spasticity was also controlled by a selective monoacyl glycerol lipase inhibitor, JZL184.
  
  
  CONCLUSIONS
  This study demonstrates definitively that FAAH inhibitors provide a new class of anti-spastic agents that may have utility in treating spasticity in MS and avoid the dose-limiting side effects associated with cannabis use.
authors.affiliation: Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Pryce
authors.forename: A
authors.initials: A
authors.lastname: Cabranes
authors.forename: J
authors.initials: J
authors.lastname: Fernández-Ruiz
authors.forename: T
authors.initials: T
authors.lastname: Bisogno
authors.forename: V
authors.initials: V
authors.lastname: Di Marzo
authors.forename: J Z
authors.initials: JZ
authors.lastname: Long
authors.forename: B F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: G
authors.initials: G
authors.lastname: Giovannoni
authors.forename: D
authors.initials: D
authors.lastname: Baker
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D063388:Endocannabinoids / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D008297:Male; D051379:Mice; D038602:Mice, Biozzi; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009128:Muscle Spasticity / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000294:innervation; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D013997:Time Factors; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D008994:Monoacylglycerol Lipases; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide
keywords: Anandamide; endocannabinoid; experimental autoimmune encephalomyelitis; fatty acid amide hydrolase; multiple sclerosis; spasticity