Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland National Centre for Biomedical Engineering Science (NCBES), Neuroscience Cluster, National University of Ireland, Galway, Ireland Centre for Pain Research, National University of Ireland, Galway, Ireland.
Pain. 2011 Nov;152(11):2495-2504. doi: 10.1016/j.pain.2011.07.014. Epub 2011 Aug 23.
The endogenous cannabinoid (endocannabinoid) system plays an important role in fear-conditioned analgesia (FCA) and expression and extinction of conditioned fear. The hippocampus has an established role in both pain and conditioned fear and is a substrate for endocannabinoid activity. This study aimed to investigate the role of the endocannabinoid system in the ventral hippocampus (vHip) in FCA and in fear responding in the presence of nociceptive tone. Fear-conditioned rats displayed significantly increased freezing and 22-kHz ultrasonic vocalisation and a reduction in formalin-evoked nociceptive behaviour (ie, FCA) upon re-exposure to a context previously paired with footshock. Tissue levels of the endocannabinoids, anandamide, and 2-arachidonoylglycerol, as well as the fatty acid amide, palmitoylethanolamide, were significantly higher in the vHip of fear-conditioned rats compared with non-fear-conditioned controls. URB597 (inhibitor of fatty acid amide hydrolase [FAAH]), administered bilaterally into the vHip, significantly enhanced FCA during the entire trial and increased fear responding in formalin-treated rats early in the trial. The URB597-induced enhancement of FCA was blocked by intra-vHip administration of the cannabinoid(1) (CB(1)) receptor antagonist/inverse agonist rimonabant. Intra-vHip rimonabant alone had no effect on the expression of FCA, and URB597 did not significantly alter formalin-evoked nociceptive behaviour in non-fear-conditioned rats. These data suggest an important role for the endocannabinoid system in the vHip in FCA, whereby levels of 2-arachidonoylglycerol and the FAAH substrates palmitoylethanolamide and anandamide are increased in rats expressing FCA, and pharmacological inhibition of FAAH in the vHip enhances this form of endogenous analgesia via a CB(1) receptor-dependent mechanism.
内源性大麻素（内源性大麻素）系统在条件性疼痛抑制（FCA）和条件性恐惧的表达和消退中发挥重要作用。海马在疼痛和条件性恐惧中都有明确的作用，并且是内源性大麻素活性的基质。本研究旨在研究内源性大麻素系统在腹侧海马（vHip）中在 FCA 中的作用，以及在疼痛刺激音存在下的恐惧反应。在重新暴露于先前与足底电击配对的环境时，条件性恐惧的大鼠表现出明显增加的冻结和 22-kHz 超声发声以及福尔马林诱发的疼痛行为（即 FCA）减少。与非恐惧条件对照相比，恐惧条件大鼠 vHip 中的内源性大麻素，花生四烯酸乙醇酰胺和 2-花生四烯酰甘油，以及脂肪酸酰胺，棕榈酰乙醇酰胺的水平明显更高。双侧 vHip 给予 URB597（脂肪酸酰胺水解酶[FAAH]抑制剂）可显著增强整个试验期间的 FCA，并在试验早期增加福尔马林处理大鼠的恐惧反应。vHip 内给予大麻素（1）（CB（1））受体拮抗剂/反向激动剂利莫那班可阻断 URB597 诱导的 FCA 增强。vHip 内单独给予利莫那班对 FCA 的表达没有影响，URB597 也没有显著改变非恐惧条件大鼠的福尔马林诱发的疼痛行为。这些数据表明 vHip 中的内源性大麻素系统在 FCA 中起着重要作用，在表达 FCA 的大鼠中，2-花生四烯酰甘油和 FAAH 底物棕榈酰乙醇酰胺和花生四烯酸乙醇酰胺的水平增加，并且 vHip 中的 FAAH 药理学抑制通过 CB（1）受体依赖性机制增强这种内源性镇痛形式。
