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）是临床试验，作为慢性疼痛治疗的阿片类药物替代方法。我们在老鼠中的工作 表明将鞘内催产素与手动疗法（即按摩）耦合优化镇痛 催产素的特性。该项目提供了通过集中精力来支持这种组合疗法的框架 在脊髓回路机制上，催产素可以减轻疼痛。我们的初步研究表明 催产素特异性的脊髓电路嵌入在先前未表征的背角中 伤害性/情感触摸电路。我们将进行三组互补的实验集，以测试整体 假设催产素通过平衡激发，抑制，伤害感和情感接触来减轻疼痛 雕刻带有负面价的脊柱投影系统的活动（与有害相关 刺激），以及与正价相关的信号（例如触摸的愉悦特性）。药理 啮齿动物的行为研究表明脊髓催产素受体（OTR）介导鞘内摄氏 催产素诱导的镇痛。在AIM 1中，我们绘制OTR+中间神经元在背角中的分布 雌性和雄性老鼠，老鼠和人类。在AIM 2中，我们映射OTR+INS的特定输入/输出概况。这里 我们检验了抑制性和兴奋性OTR+INS的假设 具有差异性调节分子定义的椎板I投射神经元的活性的信息。在 AIM 3我们分析OT脊髓回路对感官诱发的反射和情感 - 动机痛苦。对于目标3，我们实施了我们最近开发的计算方法来扩展感觉 - 反思性和情感动机疼痛。我们人类组织研究的结果将告知我们的 我们的啮齿动物研究的解释可以应用于人类疗法。基于我们在触摸方面的独特专业知识 特定的脊髓电路，访问大量脊髓特定工具的曲目以及行为分析 匹配我们电路解剖技术的粒度，我们有独特的准备来提供理论 这种组合疗法的框架。除了为旧约交付的上下文和条件提供信息外，这项工作 也可以在诊所中用于调整OT剂量和递送方法。这个项目对几个项目有影响 其他原因：1）使用计算机视觉/机器学习，我们将发现疼痛的具体方面 脊髓OT可以缓解的经验，并评估针对其他镇痛药的功效； 2）我们的 可以轻松地共享和实施客观扩展啮齿动物痛苦的计算方法 研究小组是标准化啮齿动物疼痛评估的蓝图（请参阅资源共享）； 3）我们的 通用方法和模型可以用作测试其他神经调节剂的基本蓝图 在功能上整合到触摸和伤害感受的脊髓回路中；和; 4）这种基础工作 告知创新的方法，以使感觉与痛苦的情感经历相关，激发新的感觉 疗法以独特的治疗。