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

Eur J Pharmacol. 2002 Mar 29;439(1-3):83-92. doi: 10.1016/s0014-2999(02)01369-9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonic Acids / pharmacology
  • Benzoxazines
  • Camphanes / pharmacology
  • Cannabinoid Receptor Modulators
  • Capsaicin / analogs & derivatives*
  • Capsaicin / pharmacology*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Genotype
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Morpholines / pharmacology
  • Multiple Sclerosis / physiopathology
  • Multiple Sclerosis / prevention & control
  • Muscle Spasticity / physiopathology
  • Muscle Spasticity / prevention & control*
  • Naphthalenes / pharmacology
  • Pain / physiopathology
  • Pain / prevention & control*
  • Pain Measurement
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology
  • Receptors, Cannabinoid
  • Receptors, Drug / drug effects
  • Receptors, Drug / genetics
  • Receptors, Drug / physiology
  • Rimonabant


  • Arachidonic Acids
  • Benzoxazines
  • Camphanes
  • Cannabinoid Receptor Modulators
  • Morpholines
  • Naphthalenes
  • Piperidines
  • Pyrazoles
  • Receptors, Cannabinoid
  • Receptors, Drug
  • SR 144528
  • arvanil
  • methanandamide
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • Rimonabant
  • Capsaicin