Effects of direct periaqueductal grey administration of a cannabinoid receptor agonist on nociceptive and aversive responses in rats

Neuropharmacology. 2003 Oct;45(5):594-604. doi: 10.1016/s0028-3908(03)00235-1.


The analgesic potential of cannabinoids may be hampered by their ability to produce aversive emotion when administered systemically. We investigated the hypothesis that the midbrain periaqueductal grey (PAG) is a common substrate mediating the anti-nociceptive and potential aversive effects of cannabinoids. The rat formalin test was used to model nociceptive behaviour. Intra-PAG microinjection of the excitatory amino acid D,L-homocysteic acid (DLH) was used to induce an aversive, panic-like reaction characteristic of the defensive "fight or flight" response. Administration of the cannabinoid receptor agonist HU210 (5 microg/rat) into the dorsal PAG significantly reduced the second phase of formalin-evoked nociceptive behaviour, an effect which was blocked by co-administration of the CB(1) receptor antagonist SR141716A (50 microg/rat). This anti-nociceptive effect was accompanied by an HU210-induced attenuation of the formalin-evoked increase in Fos protein expression in the caudal lateral PAG. Intra-dorsal PAG administration of HU210 (0.1, 1 or 5 microg/rat) significantly reduced the aversive DLH-induced explosive locomotor response. The anti-nociceptive effect of HU210 is likely to result from activation of the descending inhibitory pain pathway. Mechanisms mediating the anti-aversive effects of cannabinoids in the PAG remain to be elucidated. These data implicate a role for the PAG in both cannabinoid-mediated anti-nociceptive and anti-aversive responses.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Behavior, Animal
  • Cannabinoid Receptor Agonists*
  • Disinfectants
  • Dose-Response Relationship, Drug
  • Dronabinol / analogs & derivatives*
  • Dronabinol / pharmacology*
  • Dronabinol / therapeutic use
  • Drug Combinations
  • Escape Reaction / drug effects
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Excitatory Amino Acid Antagonists / therapeutic use
  • Formaldehyde
  • Homocysteine / analogs & derivatives*
  • Homocysteine / toxicity
  • Immunohistochemistry / methods
  • Male
  • Microinjections
  • Movement / drug effects
  • Pain / chemically induced
  • Pain / drug therapy*
  • Pain Measurement / drug effects
  • Periaqueductal Gray / anatomy & histology
  • Periaqueductal Gray / drug effects*
  • Piperidines / administration & dosage
  • Proto-Oncogene Proteins c-fos / metabolism
  • Pyrazoles / administration & dosage
  • Rats
  • Rats, Sprague-Dawley
  • Rimonabant
  • Time Factors


  • Cannabinoid Receptor Agonists
  • Disinfectants
  • Drug Combinations
  • Excitatory Amino Acid Antagonists
  • Piperidines
  • Proto-Oncogene Proteins c-fos
  • Pyrazoles
  • Homocysteine
  • homocysteic acid
  • Formaldehyde
  • Dronabinol
  • HU 211
  • Rimonabant