Evidence for a potential role for TRPV1 receptors in the dorsolateral periaqueductal gray in the attenuation of the anxiolytic effects of cannabinoids

Prog Neuropsychopharmacol Biol Psychiatry. 2009 Nov 13;33(8):1517-21. doi: 10.1016/j.pnpbp.2009.08.017. Epub 2009 Sep 6.


Several studies have shown anxiolytic effects of cannabinoids after systemic or central injections. The periaqueductal gray matter is a midbrain structure involved in the control of anxiety states. Intra-cerebral administration of cannabidiol, a phytocannabinoid, or anandamide, an endocannabinoid, into the dorsolateral portion of periaqueductal gray (dlPAG) promotes anxiolytic-like effects in several animal models of anxiety with bell-shaped dose-response curves. The reasons for these curves are still unclear, but since these drugs can also activate TRPV1 receptors and increase glutamate release, we hypothesized that, at high doses, cannabidiol and WIN 55,212-2, a CB1 receptor agonist, could activate TRPV1 receptors, facilitating glutamate neurotransmission and anxiety responses. To test this hypothesis male Wistar rats with cannulae aimed toward the dlPAG were submitted to the following intra-dlPAG treatments: Experiment 1. Vehicle (0.2 microL) or WIN 55,212-2 (3-30 pmol); Experiment 2. Capsazepine (CPZ, 10 nmol, a TRPV1 receptor antagonist) or vehicle followed, 5 min later, by vehicle or WIN 55, 212-2 (10 or 30 pmol); Experiment 3. CPZ (10 nmol) or vehicle followed, 5 min later, by cannabidiol (30 or 60 nmol). Ten minutes after the last injection the animals were tested in the elevated plus maze (EPM). WIN 55,212-2 and cannabidiol induced anxiolytic effects at lower doses that disappeared at the higher dose. Although CPZ+WIN 10 or CPZ+WIN 30 pmol groups were not different from control (CPZ+V), capsazepine prevented the decrease in open arm exploration caused by the higher of dose of WIN 55,212-2 (30 nmol) relative to the lower dose of WIN 55,212-2 (10 nmol) and, in the case of cannabidiol (60 nmol), increased open arm exploration (V+CBD 60 group versus CPZ+CBD 60 group). These results suggest that TRPV1 receptors in the dlPAG modulate anxiety and that activation of these receptors by high doses of cannabinoids could be involved in the bell-shaped dose-response curves observed with these compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / administration & dosage
  • Analysis of Variance
  • Animals
  • Anxiety / drug therapy*
  • Anxiety / pathology
  • Arachidonic Acids / therapeutic use
  • Benzoxazines / administration & dosage
  • Cannabinoid Receptor Modulators / agonists
  • Cannabinoid Receptor Modulators / antagonists & inhibitors
  • Cannabinoid Receptor Modulators / therapeutic use*
  • Capsaicin / administration & dosage
  • Capsaicin / analogs & derivatives
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Endocannabinoids
  • Male
  • Microinjections / methods
  • Morpholines / administration & dosage
  • Naphthalenes / administration & dosage
  • Periaqueductal Gray / drug effects*
  • Polyunsaturated Alkamides / therapeutic use
  • Rats
  • Rats, Wistar
  • TRPV Cation Channels / physiology*
  • Time Factors


  • Analgesics
  • Arachidonic Acids
  • Benzoxazines
  • Cannabinoid Receptor Modulators
  • Endocannabinoids
  • Morpholines
  • Naphthalenes
  • Polyunsaturated Alkamides
  • TRPV Cation Channels
  • Trpv1 protein, rat
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • capsazepine
  • Capsaicin
  • anandamide