title: Effects of direct periaqueductal grey administration of a cannabinoid receptor agonist on nociceptive and aversive responses in rats.
abstract: 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.
authors.affiliation: Institute of Neuroscience, School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK. david.finn@nottingham.ac.uk
authors.forename: D P
authors.initials: DP
authors.lastname: Finn
authors.forename: M D
authors.initials: MD
authors.lastname: Jhaveri
authors.forename: S R G
authors.initials: SR
authors.lastname: Beckett
authors.forename: C H
authors.initials: CH
authors.lastname: Roe
authors.forename: D A
authors.initials: DA
authors.lastname: Kendall
authors.forename: C A
authors.initials: CA
authors.lastname: Marsden
authors.forename: V
authors.initials: V
authors.lastname: Chapman
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D063386:Cannabinoid Receptor Agonists; D004202:Disinfectants; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D004338:Drug Combinations; D004924:Escape Reaction / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D005557:Formaldehyde; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000633:toxicity; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008845:Microinjections; D009068:Movement / Q000187:drug effects; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D010487:Periaqueductal Gray / Q000033:anatomy & histology / Q000187:drug effects*; D010880:Piperidines / Q000008:administration & dosage; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077285:Rimonabant; D013997:Time Factors
chemical_list: D063386:Cannabinoid Receptor Agonists; D004202:Disinfectants; D004338:Drug Combinations; D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D016760:Proto-Oncogene Proteins c-fos; D011720:Pyrazoles; D006710:Homocysteine; C007956:homocysteic acid; D005557:Formaldehyde; D013759:Dronabinol; C062018:HU 211; D000077285:Rimonabant