Itoga Christy A, Roltsch Hellard Emily A, Whitaker Annie M, Lu Yi-Ling, Schreiber Allyson L, Baynes Brittni B, Baiamonte Brandon A, Richardson Heather N, Gilpin Nicholas W
Department of Physiology, Louisiana State University Health Science Center, New Orleans, LA, USA.
Neuroscience and Behavior Program, University of Massachusetts, Amherst, MA, USA.
Neuropsychopharmacology. 2016 Sep;41(10):2463-72. doi: 10.1038/npp.2016.44. Epub 2016 Mar 25.
Hyperalgesia is an exaggerated response to noxious stimuli produced by peripheral or central plasticity. Stress modifies nociception, and humans with post-traumatic stress disorder (PTSD) exhibit co-morbid chronic pain and amygdala dysregulation. Predator odor stress produces hyperalgesia in rodents. Systemic blockade of corticotropin-releasing factor (CRF) type 1 receptors (CRFR1s) reduces stress-induced thermal hyperalgesia. We hypothesized that CRF-CRFR1 signaling in central amygdala (CeA) mediates stress-induced hyperalgesia in rats with high stress reactivity. Adult male Wistar rats were exposed to predator odor stress in a conditioned place avoidance paradigm and indexed for high (Avoiders) and low (Non-Avoiders) avoidance of predator odor-paired context, or were unstressed Controls. Rats were tested for the latency to withdraw hindpaws from thermal stimuli (Hargreaves test). We used pharmacological, molecular, and immunohistochemical techniques to assess the role of CRF-CRFR1 signaling in CeA in stress-induced hyperalgesia. Avoiders exhibited higher CRF peptide levels in CeA that did not appear to be locally synthesized. Intra-CeA CRF infusion mimicked stress-induced hyperalgesia. Avoiders exhibited thermal hyperalgesia that was reversed by systemic or intra-CeA injection of a CRFR1 antagonist. Finally, intra-CeA infusion of tetrodotoxin produced thermal hyperalgesia in unstressed rats and blocked the anti-hyperalgesic effect of systemic CRFR1 antagonist in stressed rats. These data suggest that rats with high stress reactivity exhibit hyperalgesia that is mediated by CRF-CRFR1 signaling in CeA.
痛觉过敏是由外周或中枢可塑性产生的对伤害性刺激的过度反应。应激会改变痛觉感受，患有创伤后应激障碍（PTSD）的人会出现慢性疼痛合并症和杏仁核功能失调。捕食者气味应激会在啮齿动物中产生痛觉过敏。促肾上腺皮质激素释放因子（CRF）1型受体（CRFR1s）的全身阻断可减轻应激诱导的热痛觉过敏。我们假设，在具有高应激反应性的大鼠中，中央杏仁核（CeA）中的CRF-CRFR1信号传导介导应激诱导的痛觉过敏。成年雄性Wistar大鼠在条件性位置回避范式中暴露于捕食者气味应激，并根据对捕食者气味配对环境的高（回避者）和低（非回避者）回避程度进行分类，或作为未受应激的对照组。测试大鼠从热刺激中撤回后爪的潜伏期（哈格里夫斯试验）。我们使用药理学、分子和免疫组织化学技术来评估CeA中CRF-CRFR1信号传导在应激诱导的痛觉过敏中的作用。回避者在CeA中表现出较高的CRF肽水平，这些肽似乎不是在局部合成的。向CeA内注射CRF可模拟应激诱导的痛觉过敏。回避者表现出热痛觉过敏，全身或向CeA内注射CRFR1拮抗剂可逆转这种过敏。最后，向CeA内注射河豚毒素在未受应激的大鼠中产生热痛觉过敏，并阻断了全身CRFR1拮抗剂在受应激大鼠中的抗痛觉过敏作用。这些数据表明，具有高应激反应性的大鼠表现出由CeA中的CRF-CRFR1信号传导介导的痛觉过敏。
