3-(2-hydroxy-4-(1-1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol and Multiple-Sclerosis

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.. 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.. 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.. 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.

Topics: Animals; Benzoxazines; Body Temperature; Cross Reactions; Cyclohexanols; Encephalomyelitis, Autoimmune, Experimental; Mice; Mice, Knockout; Morpholines; Multiple Sclerosis; Muscle Spasticity; Naphthalenes; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

Multiple sclerosis is increasingly being recognized as a neurodegenerative disease that is triggered by inflammatory attack of the CNS. As yet there is no satisfactory treatment. Using experimental allergic encephalo myelitis (EAE), an animal model of multiple sclerosis, we demonstrate that the cannabinoid system is neuroprotective during EAE. Mice deficient in the cannabinoid receptor CB1 tolerate inflammatory and excitotoxic insults poorly and develop substantial neurodegeneration following immune attack in EAE. In addition, exogenous CB1 agonists can provide significant neuroprotection from the consequences of inflammatory CNS disease in an experimental allergic uveitis model. Therefore, in addition to symptom management, cannabis may also slow the neurodegenerative processes that ultimately lead to chronic disability in multiple sclerosis and probably other diseases.

Topics: Animals; Aspartic Acid; Axons; Benzoxazines; Cannabinoids; Cyclohexanols; Dizocilpine Maleate; Encephalomyelitis, Autoimmune, Experimental; Excitatory Amino Acid Agonists; Gene Deletion; Humans; Mice; Mice, Transgenic; Monomeric GTP-Binding Proteins; Morpholines; Multiple Sclerosis; N-Methylaspartate; Naphthalenes; Nerve Degeneration; Nuclear Proteins; Receptors, Cannabinoid; Receptors, Drug; Receptors, N-Methyl-D-Aspartate; Retina; Saccharomyces cerevisiae Proteins; Spinal Cord; Uveitis