Parabrachial Pituitary Adenylate Cyclase-Activating Polypeptide Activation of Amygdala Endosomal Extracellular Signal-Regulated Kinase Signaling Regulates the Emotional Component of Pain.
Parabrachial Pituitary Adenylate Cyclase-Activating Polypeptide Activation of Amygdala Endosomal Extracellular Signal-Regulated Kinase Signaling Regulates the Emotional Component of Pain.
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DOI：
10.1016/j.biopsych.2016.08.025
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发表时间：
2017-04-15
影响因子：
10.6
通讯作者：
May V
中科院分区：
文献类型：
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作者：
Missig G;Mei L;Vizzard MA;Braas KM;Waschek JA;Ressler KJ;Hammack SE;May V
慢性疼痛和压力相关的精神病理学，如抑郁症和焦虑相关的异常，是相互加强的;然而，这种加强的神经元回路和机制仍然没有很好地理解。腺苷酸环化酶激活多肽（PACAP; Adcyap1）及其同源PAC 1受体（Adcyap1r1）在外周伤害性通路中表达，参与焦虑相关反应，并已被认为与创伤后应激障碍（PTSD）和其他精神健康疾病有关。使用免疫细胞化学、药物治疗和行为测试技术，我们使用啮齿动物部分坐骨神经慢性收缩模型（CCI;每个实验每组n = 5 - 8）来评估PACAP可塑性和伤害性和应激相关行为中的信号传导。我们发现，慢性神经性疼痛增加PACAP表达在多层次沿着脊髓-臂旁杏仁束。此外，CCI双侧增强伤害性杏仁核（CeA）PACAP免疫反应性，ERK磷酸化和c-Fos激活，与焦虑样行为和伤害性超敏反应的增强平行。急性CeA输注PACAP受体拮抗剂PACAP（6 - 38）阻断了CCI诱导的行为反应。此外，用MEK或内吞作用抑制剂预处理以阻断内体PACAP受体ERK信号传导减弱PACAP诱导的CeA神经元活化和伤害性反应。我们的数据表明，慢性疼痛诱导的PACAP神经可塑性和信号在脊髓-parabrachioamygdaloid预测影响CeA压力和伤害感受相关的适应不良反应，可以改善后受体拮抗剂，即使在损伤进展。因此，PACAP通路提供了一个重要的机制，潜在的交叉压力和慢性疼痛途径通过杏仁核。
Chronic pain and stress-related psychopathologies, such as depression and anxiety-associated abnormalities, are mutually reinforcing; however, the neuronal circuits and mechanisms that underlie this reinforcement are still not well understood. Pituitary adenylate cyclase activating polypeptide (PACAP; Adcyap1) and its cognate PAC1 receptor (Adcyap1r1) are expressed in peripheral nociceptive pathways, participate in anxiety-related responses and have been have been linked to posttraumatic stress disorder (PTSD) and other mental health afflictions. Using immunocytochemistry, pharmacological treatments and behavioral testing techniques, we have used a rodent partial sciatic nerve chronic constriction model (CCI; n = 5-8 per group per experiment) to evaluate PACAP plasticity and signaling in nociceptive and stress-related behaviors. We show that chronic neuropathic pain increases PACAP expression at multiple tiers along the spino-parabrachioamygdaloid tract. Furthermore, CCI bilaterally augments nociceptive amygdala (CeA) PACAP immunoreactivity, ERK phosphorylation and c-Fos activation, in parallel with heightened anxiety-like behavior and nociceptive hypersensitivity. Acute CeA infusions with the PACAP receptor antagonist PACAP(6-38) blocked CCI-induced behavioral responses. Additionally, pretreatments with inhibitors of MEK or endocytosis to block endosomal PACAP receptor ERK signaling attenuated PACAP-induced CeA neuronal activation and nociceptive responses. Our data suggest that chronic pain-induced PACAP neuroplasticity and signaling in spino-parabrachioamygdaloid projections impact CeA stress- and nociception-associated maladaptive responses which can be ameliorated upon receptor antagonism even during injury progression. Thus the PACAP pathway provides for an important mechanism underlying the intersection of stress and chronic pain pathways via the amygdala.