title: Endocannabinoid-mediated enhancement of fear-conditioned analgesia in rats: opioid receptor dependency and molecular correlates.
abstract: The opioid and endocannabinoid systems mediate analgesia expressed upon re-exposure to a contextually aversive stimulus (fear-conditioned analgesia; FCA), and modulate the mitogen-activated protein kinase (MAPK) pathway. However, an interaction between the opioid and endocannabinoid systems during FCA has not been investigated at the behavioural or molecular level. FCA was modeled in male Lister-hooded rats by assessing formalin-evoked nociceptive behaviour in an arena previously paired with footshock. Administration of the fatty acid amide hydrolase and endocannabinoid catabolism inhibitor, URB597 (0.3 mg/kg, i.p.), enhanced expression of FCA. The opioid receptor antagonist, naloxone, attenuated FCA and attenuated the URB597-induced enhancement of FCA. SR141716A (CB(1) antagonist) and SR144528 (CB(2) antagonist) also attenuated the URB597-mediated enhancement of FCA. Expression of FCA was associated with increased relative phospho-ERK2 expression in the amygdala, an effect blocked by naloxone, SR141716A, and SR144528. Furthermore, URB597-mediated enhancement of FCA was associated with reduced phospho-ERK1 and phospho-ERK2 in the amygdala. Phospho-ERK1/2 expression in the hippocampus, prefrontal cortex, and thalamus was unchanged following FCA and drug treatment. None of the drugs affected formalin-evoked nociceptive behaviour or phospho-ERK1/2 expression in non-fear-conditioned rats. These data suggest that endocannabinoid-mediated enhancement of FCA is abolished by pharmacological blockade of opioid receptors as well as CB(1) or CB(2) receptors. Both pharmacological enhancement (with URB597) and attenuation (with naloxone) of this form of endogenous analgesia were associated with reduced expression of phospho-ERK1/2 in the amygdaloid complex arguing against a causal role for ERK1/2 signaling in the amygdala during expression of FCA or its modulation by opioids or cannabinoids.
authors.affiliation: Department of Pharmacology and Therapeutics, NCBES Neuroscience Cluster and Centre for Pain Research, National University of Ireland, Galway, University Road, Galway, Ireland.
authors.forename: Ryan K
authors.initials: RK
authors.lastname: Butler
authors.forename: Kieran
authors.initials: K
authors.lastname: Rea
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Lang
authors.forename: Aisling M
authors.initials: AM
authors.lastname: Gavin
authors.forename: David P
authors.initials: DP
authors.lastname: Finn
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000698:Analgesia / Q000379:methods*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology*; D001549:Benzamides / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002219:Carbamates / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D005239:Fear / Q000187:drug effects / Q000502:physiology; D008297:Male; D009292:Narcotic Antagonists / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D010147:Pain Measurement; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D001549:Benzamides; D063385:Cannabinoid Receptor Modulators; D002219:Carbamates; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D009292:Narcotic Antagonists; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D011957:Receptors, Opioid; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C078814:anandamide