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Control of Spasticity in a Multiple Sclerosis Model is mediated by CB 1 , not CB 2 , Cannabinoid Receptors

Control of Spasticity in a Multiple Sclerosis Model is mediated by CB 1 , not CB 2 , Cannabinoid... 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 CB1 and CB2 cannabinoid receptors in the control of experimental spasticity. Experimental approach: 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. Key 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 and Implications: 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. British Journal of Pharmacology (2007) 150, 519–525. doi:10.1038/sj.bjp.0707003 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Pharmacology Wiley

Control of Spasticity in a Multiple Sclerosis Model is mediated by CB 1 , not CB 2 , Cannabinoid Receptors

British Journal of Pharmacology , Volume 150 (4) – Feb 1, 2007

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Publisher
Wiley
Copyright
2007 British Pharmacological Society
ISSN
0007-1188
eISSN
1476-5381
DOI
10.1038/sj.bjp.0707003
pmid
17220914
Publisher site
See Article on Publisher Site

Abstract

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 CB1 and CB2 cannabinoid receptors in the control of experimental spasticity. Experimental approach: 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. Key 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 and Implications: 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. British Journal of Pharmacology (2007) 150, 519–525. doi:10.1038/sj.bjp.0707003

Journal

British Journal of PharmacologyWiley

Published: Feb 1, 2007

References