Serotonin and Pain Modulation

血清素和疼痛调节

• 批准号: 10350688
• 负责人: ASAF KELLER
• 金额: $ 48.3万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10350688
• 关键词: Affect; Affective; American; Animal Model; Animals; Calcium Channel; Chemosensitization; Chronic; Coupled; Development; Diabetes Mellitus; Electrophysiology (science); Functional disorder; Goals; Heart Diseases; In Vitro; Lead; Malignant Neoplasms; Mass Spectrum Analysis; Medical; Modeling; Nerve; Neurons; Nociception; Nociceptive Stimulus; Operative Surgical Procedures; Output; Pain; Pathologic; Pathway interactions; Patients; Pharmacologic Substance; Physiological; Posterior Horn Cells; Productivity; Research; Resistance; Role; Scanning; Sensory; Serotonin; Spinal; Stimulus; Structure of trigeminal nerve spinal tract nucleus; System; Testing; Trigeminal Nuclei; Trigeminal System; animal pain; base; chronic constriction injury; chronic pain; chronic pain management; chronic pain patient; chronic painful condition; cost; design; dorsal horn; in vivo; neurophysiology; novel; novel therapeutics; optogenetics; pain perception; pain signal; postsynaptic; prevent; programs; receptor; response; sensory stimulus; therapy resistant; voltage

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.

项目摘要/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 很大程度上是因为他们慢性疼痛状况的潜在病理生理学尚不清楚。终极的 这项研究计划的目标就是填补这一关键空白。痛觉由嘴腹侧延髓强烈调节 (RVM)直接调节伤害性背角神经元的活动。右室突出的是5-羟色胺- 含有神经元的。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 5-羟色胺输出的病理性增加和减少。我们令人兴奋的初步发现--使用一个模型 眼眶下神经慢性压迫性损伤后的慢性疼痛(CCI-Pain)--可能会解决这个问题 重要的争议。我们发现，在CCI-Pain中，RVM-5HT神经元的活性被放大，导致 尾侧背角-三叉神经核(SpVc)中5-羟色胺的异常高释放。这会导致SpVc 神经元产生一连串的后放电(ADS)，远远超过伤害性刺激，这是 被认为是慢性疼痛的表现。增加的5-羟色胺释放也增强了 SpVc神经元的伤害性输入。再加上我们之前的演示，降低体内5-羟色胺水平 RVM抑制ADS并阻断疼痛敏感化，我们假设5-羟色胺能驱动从 RVM引起背角神经元的过度兴奋，从而导致慢性疼痛。AIM I测试 假设5HT-RVM神经元的活动被放大导致SpVc中5HT的释放增加，并且 慢性疼痛的发展。我们验证了光遗传学的电生理活动-- 在CCI-Pain中，已发现的5HTRVm-&SpVc投射神经元被放大。我们也会在体内快速使用 扫描伏安法和定量质谱仪，以验证CCI-Pain相关的预测 SpVc的5-羟色胺释放增加。AIM II验证了5-羟色胺释放增加是有因果关系的假设 与慢性疼痛的发展有关。我们将测试体内5-羟色胺光遗传释放的预测 SpVc中的RVM终末会导致感觉和情感疼痛的迹象，这些迹象会因 重复5-羟色胺释放。我们还将测试反向预测，即这些5-羟色胺的光遗传抑制 终末期可缓解CCI-疼痛。Aim III验证了放大的5-羟色胺活性产生 通过在背角神经元诱导异常ADS而引起的慢性疼痛。我们将测试在活体内的预测 5-羟色胺的光遗传释放可诱导未损伤动物SpVc神经元的ADS，而光遗传抑制 5-羟色胺的释放将抑制CCI-Pain动物的ADS。目的验证放大5-羟色胺活性的假说 通过增强对背角神经元的初级传入输入而产生慢性疼痛。我们将测试 预测在体外5-羟色胺的光遗传释放会引起三叉神经传入SpVc神经元的增强。 预测的结果对开发新的治疗药物具有新的翻译相关性。 慢性疼痛。