Cannabinoids control spasticity and tremor in a multiple sclerosis model

Abstract

Chronic relapsing experimental allergic encephalomyelitis (CREAE) is an autoimmune model of multiple sclerosis. Although both these diseases are typified by relapsing-remitting paralytic episodes, after CREAE induction by sensitization to myelin antigens Biozzi ABH mice also develop spasticity and tremor. These symptoms also occur during multiple sclerosis and are difficult to control. This has prompted some patients to find alternative medicines, and to perceive benefit from cannabis use. Although this benefit has been backed up by small clinical studies, mainly with non-quantifiable outcomes, the value of cannabis use in multiple sclerosis remains anecdotal. Here we show that cannabinoid (CB) receptor agonism using R(+)-WIN 55,212, delta9-tetrahydrocannabinol, methanandamide and JWH-133 (ref. 8) quantitatively ameliorated both tremor and spasticity in diseased mice. The exacerbation of these signs after antagonism of the CB1 and CB2 receptors, notably the CB1 receptor, using SR141716A and SR144528 (ref. 8) indicate that the endogenous cannabinoid system may be tonically active in the control of tremor and spasticity. This provides a rationale for patients' indications of the therapeutic potential of cannabis in the control of the symptoms of multiple sclerosis, and provides a means of evaluating more selective cannabinoids in the future.

Cannabinoids and Tremor Induced by Motor-related Disorders: Friend or Foe?

“…Involvement of the endocannabinoid system acting at CB 1 R in the pathogenesis of MS have been supported by several studies [87][88][89][90]. There are now several lines of evidence indicative of therapeutic potentials of cannabinoids in the control of MSrelated symptoms, including tremor, which remains difficult to manage with current medications (e.g., carbamazepine, propranolol, primidone, and gluthetimide) [12,89,91,92]. Following this premise, De Lago et al [93] have shown that the nonselective cannabinoid agonist WIN 55,212-2 ameliorated neurological disability, tremor, and spasticity in the chronic relapsing experimental autoimmune encephalomyelitis murine model of MS [92].…”

“…Correspondingly, this study revealed the prominent role of CB 1 R activation in the relief of tremor and spasticity, as a selective CB 1 R, but not a CB 2 R, antagonist reversed the positive effects of preadministered cannabinoids; moreover, no beneficial effects were observed by administering a selective CB 2 agonist [93,94]. An earlier study reported that cannabinoid agonists Δ 9 -THC, methanandamide, R(+)WIN 55,212-2, and JWH-133 all diminished tremor and spasticity in the experimental autoimmune encephalomyelitis model, and that aggravation of the symptoms occurred after using CB 2 R and, in particular, CB 1 R antagonists [12].…”

“…In a systematic review published by Koppel et al [100], oral cannabis extract and Δ 9 -THC was considered, at present, Bprobably ineffective^and Sativex (nabiximols) Bpossibly ineffective^for easing MS-related tremors [100]. Although a decrease in CB 1 R density has been found in caudate-putamen and cortical regions, there are still lack of convincing data on changes to CB 1 R and CB 2 R expression and endocannabinoid transmission in both animals and postmortem brain of patients suffering from MS [12,101].…”

“…To date, >100 terpenophenolic cannabinoids have been isolated from C. sativa, among these, Δ 9 -tetrahydrocannabinol (Δ 9 -THC), as the primary and main psychoactive constituent, cannabidiol (CBD), cannabinol, cannabichromene, and cannabigerol are of particular interest [4][5][6]. In the light of previous studies, the cannabis plant has been shown to play a role as an antiemetic, appetite stimulant, analgesic, euphoriant, anti-inflammatory agent, anticonvulsant, and as a sedative [2,4,[7][8][9][10][11][12][13][14][15][16][17][18][19][20]. It has also been noted that cannabis can impair memory and cognition [21,22].…”

Cannabis and endocannabinoid modulators: Therapeutic promises and challenges

“…A variant of EAE and second model of MS, chronic relapsing experimental allergic encephalomyelitis (CREAE), has shown very robust sensitivity to cannabinoid agents as well. For example, Baker et al [120] have investigated the role of CB1 vs. CB2 cannabinoid receptors in cannabinoid-induced suppression of the spasticity and tremor of mice with CREAE, reporting that both CB1 and CB2 receptors may play a role-CB2 possibly through their presence on immune cells in the CNS which may be signaled to down-regulate their reactivity through cannabinoid agonism [120,121].…”