Serotonin and Pain Modulation

项目总结/摘要 慢性疼痛是患者最常见的主诉。大多数慢性疼痛患者对治疗有抵抗力， 这在很大程度上是因为他们的慢性疼痛状况的潜在病理生理学是未知的。最终 这项研究计划的目标是填补这一关键空白。延髓的喙腹侧区对疼痛有很强的调节作用 (RVM)直接调节背角伤害感受神经元的活动。在右心室肥大中主要是血清素- 含有神经元。然而，这些神经元在慢性疼痛中的作用仍然存在争议，有证据表明， 病理性增加和减少的5 HT输出。我们激动人心的初步发现-使用一个模型 眶下神经慢性压迫性损伤后的慢性疼痛（CCI疼痛）-可以解决这个问题 重大争议。我们发现，在CCI-Pain中，RVM-5HT神经元活性被放大，导致 三叉神经背角尾侧核（SpVc）5-HT异常高释放。这导致SpVc 神经元产生大量的后放电（AD），其持续时间远远超过伤害性刺激， 被认为是慢性疼痛的表现。增加的5HT释放也增强了 SpVc神经元的伤害性输入。再加上我们之前的证明，减少5羟色胺水平， RVM抑制AD并阻断疼痛敏感化，我们假设， RVM导致背角神经元过度兴奋，导致慢性疼痛。目标I测试 假设5-HT-RVM神经元的活性增强导致SpVc中5-HT释放增加， 慢性疼痛的发展。我们测试了光遗传学的电生理活动的预测- 鉴定的5HT RVM-> SpVc投射神经元在CCI-Pain中扩增。我们也会用in vivo fast 扫描伏安法和定量质谱法，以测试CCI-疼痛相关的预测 SpVc中5-HT释放量增加。目的II检验增加的5-HT释放与 慢性疼痛的发展。我们将测试预测，在体内光遗传释放的5 HT从 SpVc中的RVM终末导致感觉和情感疼痛的体征，并且这些体征会因 重复5HT释放。我们也将测试相反的预测，即这些5HT的光遗传学抑制 终端的结果从CCI疼痛缓解。目的III测试5 HT活性增强产生的假设 慢性疼痛通过诱导背角神经元的异常AD。我们将在体内测试预测， 5 HT的光遗传学释放诱导未损伤动物SpVc神经元中的AD，并且光遗传学抑制 5HT释放的量将抑制CCI-疼痛动物中的AD。目的IV检验5-HT活性增强的假设 通过增强对背角神经元的初级传入输入产生慢性疼痛。我们将测试 预测5 HT在体外的光遗传学释放引起三叉神经输入到SpVc神经元的增强。 预测的结果对于开发新的药物治疗具有新的翻译相关性。 慢性疼痛

Project Summary/Abstract Chronic pain is the most common complaint of patients. Most chronic pain patients are resistant to therapy, in large part because the underlying pathophysiology of their chronic pain condition is unknown. The ultimate goal of this research program is to fill this critical gap. Pain is strongly modulated by the rostroventral medulla (RVM) that directly regulates the activity of nociceptive dorsal horn neurons. Prominent in RVM are serotonin- containing neurons. However, the role of these neurons in chronic pain remains controversial, with evidence for both pathological increases and decreases in 5HT output. Our exciting preliminary findings—using a model of chronic pain after chronic constriction injury of the infraorbital nerve (CCI-Pain)—may resolve this important controversy. We show that, in CCI-Pain, RVM-5HT neuronal activity is amplified, resulting in abnormally high release of 5HT in the caudal dorsal horn – trigeminal nucleus (SpVc). This causes SpVc neurons to produce a barrage of after-discharges (ADs) that far outlast nociceptive stimuli, and that are considered a manifestation of chronic pain. The increased 5HT release also potentiates the strength of nociceptive inputs to SpVc neurons. Coupled with our previous demonstration that reducing 5HT levels in RVM suppresses ADs and blocks pain sensitization, we hypothesize that increased serotonergic drive from RVM causes hyperexcitability of dorsal horn neurons, which results in chronic pain. Aim I tests the hypothesis that amplified activity of 5HT-RVM neurons results in increased release of 5HT in SpVc and the development of chronic pain. We test the prediction that the electrophysiological activity of optogenetically- identified 5HT RVM –> SpVc projection neurons is amplified in CCI-Pain. We will also use in vivo fast scanning voltammetry, and quantitative mass spectrometry, to test the prediction that CCI-Pain is associated with increased 5HT release in SpVc. Aim II tests the hypothesis that increased 5HT release is causally related to the development of chronic pain. We will test the prediction that in vivo optogenetic release of 5HT from RVM terminals in SpVc results in signs of sensory and affective pain, and that these signs are exacerbated by repeated 5HT release. We will also test the converse prediction, that optogenetic inhibition of these 5HT terminals results in relief from CCI-Pain. Aim III tests the hypothesis that amplified 5HT activity produces chronic pain by inducing abnormal ADs in dorsal horn neurons. We will test the prediction that in vivo optogenetic release of 5HT induces ADs in SpVc neurons of uninjured animals, and that optogenetic inhibition of 5HT release will suppress ADs in CCI-Pain animals. Aim IV tests the hypothesis that amplified 5HT activity produces chronic pain by potentiating primary afferent inputs to dorsal horn neurons. We will test the prediction that optogenetic release of 5HT in vitro evokes potentiation of trigeminal inputs to SpVc neurons. The predicted findings have novel translational relevance for the development of new pharmaceuticals to treat chronic pain.