Butler Ryan K, Rea Kieran, Lang Yvonne, Gavin Aisling M, Finn David P
Department of Pharmacology and Therapeutics, NCBES Neuroscience Cluster and Centre for Pain Research, National University of Ireland, Galway, University Road, Galway, Ireland.
Pain. 2008 Dec;140(3):491-500. doi: 10.1016/j.pain.2008.10.002. Epub 2008 Nov 11.
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.
阿片类和内源性大麻素系统介导再次暴露于情境性厌恶刺激时所表现出的镇痛作用（恐惧条件性镇痛；FCA），并调节丝裂原活化蛋白激酶（MAPK）通路。然而，在行为或分子水平上，尚未研究FCA过程中阿片类和内源性大麻素系统之间的相互作用。通过评估在先前与足部电击配对的场地中福尔马林诱发的伤害性感受行为，在雄性利斯特戴帽大鼠中建立FCA模型。给予脂肪酸酰胺水解酶和内源性大麻素分解代谢抑制剂URB597（0.3mg/kg，腹腔注射）可增强FCA的表达。阿片受体拮抗剂纳洛酮可减弱FCA，并减弱URB597诱导的FCA增强作用。SR141716A（CB(1)拮抗剂）和SR144528（CB(2)拮抗剂）也减弱了URB597介导的FCA增强作用。FCA的表达与杏仁核中相对磷酸化ERK2表达增加有关，这一作用被纳洛酮、SR141716A和SR144528阻断。此外，URB597介导的FCA增强作用与杏仁核中磷酸化ERK1和磷酸化ERK2减少有关。FCA和药物处理后，海马体、前额叶皮质和丘脑中的磷酸化ERK1/2表达未发生变化。在未进行恐惧条件化的大鼠中，这些药物均未影响福尔马林诱发的伤害性感受行为或磷酸化ERK1/2表达。这些数据表明，阿片受体以及CB(1)或CB(2)受体的药理学阻断可消除内源性大麻素介导的FCA增强作用。这种内源性镇痛的药理学增强（使用URB597）和减弱（使用纳洛酮）均与杏仁核复合体中磷酸化ERK1/2表达减少有关，这表明在FCA表达或其被阿片类或大麻素调节过程中，ERK1/2信号在杏仁核中不具有因果作用。
