Refining oxytocin therapy for pain: context is key

完善催产素治疗疼痛的方法：背景是关键

• 批准号: 10595113
• 负责人: Victoria Eugenia Guadalupe Abraira
• 金额: $ 56.44万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595113
• 关键词: Absence of pain sensation; Affective; Analgesics; Animals; Anterolateral; Behavior; Behavior Therapy; Behavioral; Behavioral Assay; Biological Assay; Brain; Chronic; Clinic; Clinical Trials; Combined Modality Therapy; Computer Vision Systems; Coupling; Data; Dimensions; Dissection; Electrophysiology (science); Female; Histologic; Human; Image; Interneurons; Learning; Machine Learning; Manipulative Therapies; Maps; Massage; Mechanoreceptors; Mediating; Methods; Modeling; Molecular; Morphology; Motivation; Mus; Negative Valence; Nervous System; Neuromodulator; Neurons; Neuropeptides; Nociception; Nociceptors; Opioid; Output; Oxytocin; Oxytocin Receptor; Pain; Pain Measurement; Pain management; Peripheral; Pharmacology Study; Physiology; Positive Valence; Preparation; Property; Rattus; Reflex action; Reproducibility; Research; Resource Sharing; Rodent; Rodent Model; Sensory; Shapes; Signal Transduction; Skin; Social Behavior; Social Interaction; Spinal; Spinal Cord; Standardization; Stimulus; Synapses; System; Techniques; Testing; Touch sensation; Translating; Vertebral column; Work; autistic children; behavioral study; brain circuitry; chronic pain management; differential expression; dorsal horn; dosage; efficacy evaluation; emotional experience; experience; experimental study; genetic approach; human tissue; injured; innovation; male; novel; novel therapeutics; pharmacologic; pre-clinical; receptor; receptor expression; response; sensory stimulus; social learning; tool; two-photon

Intrathecal oxytocin (OT) is in clinical trials as an opioid alternative for chronic pain treatment. Our work in mice suggests that coupling intrathecal oxytocin with manual therapies (i.e. massage) optimizes the analgesic properties of oxytocin. This project provides the framework to support this combination therapy by concentrating on the spinal cord circuit mechanisms by which oxytocin alleviates pain. Our preliminary studies suggest that oxytocin-specific spinal cord circuits are embedded within a previously uncharacterized dorsal horn nociceptive/affective touch circuit. We will carry out three complementary sets of experiments to test the overall hypothesis that oxytocin alleviates pain by balancing excitation, inhibition, nociception, and affective touch to sculpt the activity of spinal projections systems that carry both negative valences (associated with noxious stimuli), and signals associated with positive valence (like the pleasurable properties of touch). Pharmacological and behavioral studies in rodents suggest that spinal cord oxytocin receptors (OTRs) mediate intrathecal oxytocin-induced analgesia. In Aim 1 we map the distribution of OTR+ interneurons within the dorsal horn of female and male mice, rats, and humans. In Aim 2, we map the specific input/output profiles of OTR+INs. Here we test the hypothesis that inhibitory and excitatory OTR+INs integrate peripheral nociceptive/affective touch information with OT to differentially regulate the activity of molecularly defined Lamina I projection neurons. In Aim 3 we assay the contribution of OT spinal cord circuits to both sensory-evoked reflexes and affective- motivational pain. For Aim 3 we implement our recently developed computational approaches to scale sensory- reflexive and affective-motivational pain. Results from our human tissue studies will inform how our interpretations of our rodent studies may be applied to human therapies. Based on our unique expertise in touch- specific spinal cord circuits, access to a large repertoire of spinal cord-specific tools, and behavior analytics that match the granularity of our circuit dissection techniques, we are uniquely poised to provide the theoretical framework for this combination therapy. In addition to informing context and condition for OT delivery, this work may also be used in the clinic to adjust OT dosage and delivery method. This project is impactful for several other reasons: 1) using computer vision/machine learning we will uncover the specific aspects of the pain experience that are alleviated by spinal cord OT, and assess efficacy against other analgesics; 2) our computational approaches to objectively scale rodent pain can be easily shared and implemented across research groups, serving as a blueprint to standardize rodent pain assessment (see Resource Sharing); 3) our general approach and model can serve as a basic blueprint for testing how other neuromodulators are functionally integrated into spinal cord circuits of touch and nociception; and; 4) this type of foundational work informs innovative approaches to disentangle the sensory from the emotional experiences of pain, inspiring new therapies to treat each uniquely.

鞘内催产素 (OT) 正在临床试验中作为慢性疼痛治疗的阿片类药物替代品。我们在老鼠身上的工作 表明鞘内注射催产素与手法治疗（即按摩）相结合可优化镇痛效果 催产素的性质。该项目通过集中精力提供了支持这种联合疗法的框架 关于催产素减轻疼痛的脊髓回路机制。我们的初步研究表明 催产素特异性脊髓回路嵌入先前未表征的背角内 伤害性/情感性触摸电路。我们将进行三组互补的实验来测试整体 假设催产素通过平衡兴奋、抑制、伤害感受和情感触摸来减轻疼痛 塑造携带负价的脊柱投射系统的活动（与有害物质相关） 刺激），以及与正价相关的信号（如触摸的愉悦特性）。药理作用 啮齿动物的行为研究表明脊髓催产素受体（OTR）介导鞘内 催产素诱导的镇痛。在目标 1 中，我们绘制了 OTR+ 中间神经元在背角内的分布图。 雌性和雄性小鼠、大鼠和人类。在目标 2 中，我们映射 OTR+IN 的特定输入/输出配置文件。这里 我们测试了抑制性和兴奋性 OTR+IN 整合外周伤害性/情感性触摸的假设 信息与 OT 差异调节分子定义的 Lamina I 投射神经元的活动。在 目标 3 我们分析了 OT 脊髓回路对感觉诱发反射和情感反射的贡献 动机上的痛苦。对于目标 3，我们实施了最近开发的计算方法来扩展感官- 反射性疼痛和情感动机性疼痛。我们的人体组织研究结果将告诉我们如何 我们对啮齿动物研究的解释可能适用于人类治疗。基于我们在触摸方面的独特专业知识- 特定的脊髓回路、使用大量脊髓特定工具以及行为分析 与我们电路剖析技术的粒度相匹配，我们独特地准备提供理论 这种联合疗法的框架。除了告知 OT 交付的背景和条件外，这项工作 也可用于临床调整OT剂量和给药方式。这个项目对很多人都有影响 其他原因：1）使用计算机视觉/机器学习，我们将揭示疼痛的具体方面 通过脊髓 OT 缓解的经验，并评估相对于其他镇痛药的疗效； 2）我们的 客观衡量啮齿动物疼痛的计算方法可以轻松共享和实施 研究小组，作为啮齿动物疼痛评估标准化的蓝图（见资源共享）； 3）我们的 一般方法和模型可以作为测试其他神经调节剂的基本蓝图 功能性地整合到脊髓的触觉和伤害感受回路中；和; 4）此类基础工作 提供创新方法，将感官与痛苦的情感体验分开，激发新的灵感 治疗方法独特。