Arvanil-induced inhibition of spasticity and persistent pain: evidence for therapeutic sites of action different from the vanilloid VR1 receptor and cannabinoid CB(1)/CB(2) receptors.
Activation of cannabinoid receptors causes inhibition of spasticity, in a mouse model of multiple sclerosis, and of persistent pain, in the rat formalin test. The endocannabinoid anandamide inhibits spasticity and persistent pain. It not only binds to cannabinoid receptors but is also a full agonist at vanilloid receptors of type 1 (VR1). We found here that vanilloid VR1 receptor agonists (capsaicin and N-N'-(3-methoxy-4-aminoethoxy-benzyl)-(4-tert-butyl-benzyl)-urea [SDZ-249-665]) exhibit a small, albeit significant, inhibition of spasticity that can be attenuated by the vanilloid VR1 receptor antagonist, capsazepine. Arvanil, a structural "hybrid" between capsaicin and anandamide, was a potent inhibitor of spasticity at doses (e.g. 0.01 mg/kg i.v.) where capsaicin and cannabinoid CB(1) receptor agonists were ineffective. The anti-spastic effect of arvanil was unchanged in cannabinoid CB(1) receptor gene-deficient mice or in wildtype mice in the presence of both cannabinoid and vanilloid receptor antagonists. Likewise, arvanil (0.1-0.25 mg/kg) exhibited a potent analgesic effect in the formalin test, which was not reversed by cannabinoid and vanilloid receptor antagonists. These findings suggest that activation by arvanil of sites of action different from cannabinoid CB(1)/CB(2) receptors and vanilloid VR1 receptors leads to anti-spastic/analgesic effects that might be exploited therapeutically.
Brooks
Jason W
JW
Pain Research Group, Department of Anaesthetics, Faculty of Medicine, Imperial College, Chelsea and Westminster Hospital Campus, London, UK.
Pryce
Gareth
G
Bisogno
Tiziana
T
Jaggar
Siân I
SI
Hankey
Deborah J R
DJ
Brown
Peter
P
Bridges
Daniel
D
Ledent
Catherine
C
Bifulco
Maurizio
M
Rice
Andrew S C
AS
Di Marzo
Vincenzo
V
Baker
David
D
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D048588:Benzoxazines; D001892:Camphanes / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009103:Multiple Sclerosis / Q000503:physiopathology / Q000517:prevention & control; D009128:Muscle Spasticity / Q000503:physiopathology / Q000517:prevention & control*; D009281:Naphthalenes / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology / Q000517:prevention & control*; D010147:Pain Measurement; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000077285:Rimonabant
D001095:Arachidonic Acids; D048588:Benzoxazines; D001892:Camphanes; D063385:Cannabinoid Receptor Modulators; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C110630:SR 144528; C121153:arvanil; C088155:methanandamide; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000077285:Rimonabant; D002211:Capsaicin