Dual effect of cannabinoid CB1 receptor stimulation on a vanilloid VR1 receptor-mediated response

Cell Mol Life Sci. 2003 Mar;60(3):607-16. doi: 10.1007/s000180300052.


Cannabinoid CB1 receptors and vanilloid VR1 receptors are co-localized to some extent in sensory neurons of the spinal cord and dorsal root ganglia. In this study, we over-expressed both receptor types in human embryonic kidney (HEK)-293 cells and investigated the effect of the CB1 agonist HU-210 on the VR1-mediated increase in intracellular Ca2+ ([Ca2+]i), a well-known response of the prototypical VR1 agonist capsaicin. After a 5-min pre-treatment, HU-210 (0.1 microM) significantly enhanced the effect of several concentrations of capsaicin on [Ca2+]i in HEK-293 cells over-expressing both rat CB1 and human VR1 (CB1-VR1-HEK cells), but not in cells over-expressing only human VR1 (VR1-HEK cells). This effect was blocked by the CB1 receptor antagonist SR141716A (0.5 microM), and by phosphoinositide-3-kinase and phospholipase C inhibitors. The endogenous agonist of CB1 and VR1 receptors, anandamide, was more efficacious in inducing a VR1-mediated stimulation of [Ca2+]i in CB1-VR1-HEK cells than in VR1-HEK cells, and part of its effect on the former cells was blocked by SR141716A (0.5 microM). Pre-treatment of CB1-VR1-HEK cells with forskolin, an adenylate cyclase activator, enhanced the capsaicin effect on [Ca2+]i. HU-210, which in the same cells inhibits forskolin-induced enhancement of cAMP levels, blocked the stimulatory effect of forskolin on capsaicin. Our data suggest that in cells co-expressing both CB1 and VR1 receptors, pre-treatment with CB1 agonists inhibits or stimulates VR1 gating by capsaicin depending on whether or not cAMP-mediated signalling has been concomitantly activated.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arachidonic Acids / pharmacology
  • Calcium / metabolism*
  • Calcium Channel Blockers / pharmacology
  • Cannabinoids / pharmacology
  • Capsaicin / metabolism
  • Cyclic AMP / metabolism
  • Dronabinol / analogs & derivatives*
  • Dronabinol / pharmacology
  • Endocannabinoids
  • Humans
  • Polyunsaturated Alkamides
  • Receptors, Cannabinoid
  • Receptors, Drug / agonists
  • Receptors, Drug / metabolism*


  • Arachidonic Acids
  • Calcium Channel Blockers
  • Cannabinoids
  • Endocannabinoids
  • Polyunsaturated Alkamides
  • Receptors, Cannabinoid
  • Receptors, Drug
  • Dronabinol
  • Cyclic AMP
  • HU 211
  • Capsaicin
  • Calcium
  • anandamide