Gaspar Jessica C, Okine Bright N, Llorente-Berzal Alvaro, Roche Michelle, Finn David P
Pharmacology and Therapeutics Department, National University of Ireland Galway, University Road, H91 W5P7 Galway, Ireland.
Galway Neuroscience Centre, National University of Ireland Galway, University Road, H91 W5P7 Galway, Ireland.
Molecules. 2020 Feb 24;25(4):1007. doi: 10.3390/molecules25041007.
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors with three isoforms (PPARα, PPARβ/δ, PPARγ) and can regulate pain, anxiety, and cognition. However, their role in conditioned fear and pain-fear interactions has not yet been investigated. Here, we investigated the effects of systemically administered PPAR antagonists on formalin-evoked nociceptive behaviour, fear-conditioned analgesia (FCA), and conditioned fear in the presence of nociceptive tone in rats. Twenty-three and a half hours following fear conditioning to context, male Sprague-Dawley rats received an intraplantar injection of formalin and intraperitoneal administration of vehicle, PPARα (GW6471), PPARβ/δ (GSK0660) or PPARγ (GW9662) antagonists, and 30 min later were re-exposed to the conditioning arena for 15 min. The PPAR antagonists did not alter nociceptive behaviour or fear-conditioned analgesia. The PPARα and PPARβ/δ antagonists prolonged context-induced freezing in the presence of nociceptive tone without affecting its initial expression. The PPARγ antagonist potentiated freezing over the entire trial. In conclusion, pharmacological blockade of PPARα and PPARβ/δ in the presence of formalin-evoked nociceptive tone, impaired short-term, within-trial fear-extinction in rats without affecting pain response, while blockade of PPARγ potentiated conditioned fear responding. These results suggest that endogenous signalling through these three PPAR isoforms may reduce the expression of conditioned fear in the presence of nociceptive tone.
过氧化物酶体增殖物激活受体（PPARs）是具有三种亚型（PPARα、PPARβ/δ、PPARγ）的核受体，可调节疼痛、焦虑和认知。然而，它们在条件性恐惧和疼痛-恐惧相互作用中的作用尚未得到研究。在此，我们研究了全身给予PPAR拮抗剂对福尔马林诱发的伤害性感受行为、恐惧条件性镇痛（FCA）以及大鼠在伤害性刺激存在时的条件性恐惧的影响。在对环境进行恐惧条件化23.5小时后，雄性Sprague-Dawley大鼠接受足底内注射福尔马林，并腹腔注射溶剂、PPARα拮抗剂（GW6471）、PPARβ/δ拮抗剂（GSK0660）或PPARγ拮抗剂（GW9662），30分钟后将其重新置于条件化场地15分钟。PPAR拮抗剂未改变伤害性感受行为或恐惧条件性镇痛。PPARα和PPARβ/δ拮抗剂在伤害性刺激存在的情况下延长了环境诱导的僵住时间，但不影响其初始表达。PPARγ拮抗剂在整个试验过程中增强了僵住反应。总之，在福尔马林诱发的伤害性刺激存在的情况下，对PPARα和PPARβ/δ进行药理学阻断，会损害大鼠在试验中的短期恐惧消退，而不影响疼痛反应，而阻断PPARγ则增强了条件性恐惧反应。这些结果表明，通过这三种PPAR亚型的内源性信号传导可能会在伤害性刺激存在的情况下降低条件性恐惧的表达。
