Refining oxytocin therapy for pain: context is key

鞘内催产素（OT）作为慢性疼痛治疗的阿片类药物替代品正在临床试验中。我们在小鼠中的工作 表明鞘内催产素与手动疗法（即按摩）相结合可优化镇痛效果 催产素的特性该项目提供了一个框架，以支持这种联合治疗， 脊髓回路的机制，催产素减轻疼痛。我们的初步研究表明， 催产素特异性脊髓回路嵌入在先前未表征的背角内 伤害感受/情感触摸回路。我们将进行三组互补的实验，以测试整体 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， 塑造脊柱投射系统的活动，这些系统携带负价（与有害的 刺激），以及与积极效价相关的信号（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（OTRs）介导鞘内 催产素诱导的镇痛在目的1中，我们绘制了OTR+中间神经元在脊髓背角内的分布， 雌性和雄性小鼠、大鼠和人类。在目标2中，我们映射了OTR+ IN的特定输入/输出配置文件。 我们检验了抑制性和兴奋性OTR+INs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板层I投射神经元的活动。在 目的3研究OT脊髓回路对感觉诱发反射和情感反射的作用。 动机的痛苦对于目标3，我们实现了我们最近开发的计算方法来衡量感官- 反射性和情感性的痛苦我们的人体组织研究结果将告诉我们， 我们的啮齿动物研究的解释可以应用于人类治疗。基于我们在触摸方面的独特专长- 特定的脊髓回路，获得大量脊髓特定工具，以及 匹配我们的电路解剖技术的粒度，我们是唯一准备提供理论 这一联合疗法的框架。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。这个项目对几个人都有影响。 其他原因：1）使用计算机视觉/机器学习，我们将揭示疼痛的特定方面 脊髓OT缓解的经验，并评估对其他镇痛药的疗效; 2）我们的 客观地衡量啮齿动物疼痛的计算方法可以很容易地在 研究小组，作为标准化啮齿动物疼痛评估的蓝图（见资源共享）; 3）我们的 一般的方法和模型可以作为一个基本的蓝图，用于测试其他神经调质是如何 在功能上集成到触摸和伤害感受的脊髓回路中;以及; 4）这种类型的基础工作 通知创新的方法，以解开感官从痛苦的情感体验，激发新的 独特的治疗方法。

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.