title: The endocannabinoid system in the rat dorsolateral periaqueductal grey mediates fear-conditioned analgesia and controls fear expression in the presence of nociceptive tone.
abstract: OBJECTIVE
  Endocannabinoids in the midbrain periaqueductal grey (PAG) modulate nociception and unconditioned stress-induced analgesia; however, their role in fear-conditioned analgesia (FCA) has not been examined. The present study examined the role of the endocannabinoid system in the dorsolateral (dl) PAG in formalin-evoked nociceptive behaviour, conditioned fear and FCA in rats.
  
  
  METHODS
  Rats received intra-dlPAG administration of the CB(1) receptor antagonist/inverse agonist rimonabant, or vehicle, before re-exposure to a context paired 24 h previously with foot shock. Formalin-evoked nociceptive behaviour and fear-related behaviours (freezing and 22 kHz ultrasonic vocalization) were assessed. In a separate cohort, levels of endocannabinoids [2-arachidonoyl glycerol (2-AG) and N-arachidonoyl ethanolamide (anandamide; AEA)] and the related N-acylethanolamines (NAEs) [N-palmitoyl ethanolamide (PEA) and N-oleoyl ethanolamide (OEA)] were measured in dlPAG tissue following re-exposure to conditioned context in the presence or absence of formalin-evoked nociceptive tone.
  
  
  RESULTS
  Re-exposure of rats to the context previously associated with foot shock resulted in FCA. Intra-dlPAG administration of rimonabant significantly attenuated FCA and fear-related behaviours expressed in the presence of nociceptive tone. Conditioned fear without formalin-evoked nociceptive tone was associated with increased levels of 2-AG, AEA, PEA and OEA in the dlPAG. FCA was specifically associated with an increase in AEA levels in the dlPAG.
  
  
  CONCLUSIONS
  Conditioned fear to context mobilises endocannabinoids and NAEs in the dlPAG. These data support a role for endocannabinoids in the dlPAG in mediating the potent suppression of pain responding which occurs during exposure to conditioned aversive contexts.
  
  
  BACKGROUND
  This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.
authors.affiliation: Pharmacology and Therapeutics Physiology, School of Medicine NCBES Neuroscience Cluster Centre for Pain Research, National University of Ireland, Galway, Ireland.
authors.forename: W M
authors.initials: WM
authors.lastname: Olango
authors.forename: M
authors.initials: M
authors.lastname: Roche
authors.forename: G K
authors.initials: GK
authors.lastname: Ford
authors.forename: B
authors.initials: B
authors.lastname: Harhen
authors.forename: D P
authors.initials: DP
authors.lastname: Finn
mesh_terms: D000698:Analgesia; D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D003213:Conditioning, Psychological / Q000502:physiology; D063388:Endocannabinoids; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D005557:Formaldehyde; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology*; D010487:Periaqueductal Gray / Q000187:drug effects / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000502:physiology; D000077285:Rimonabant; D014465:Ultrasonics
chemical_list: D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D005557:Formaldehyde; D000077285:Rimonabant