Rodent model to distinguish between facial itch and pain

描述(由申请人提供)：慢性瘙痒是一种重要的临床问题，与许多皮肤病和系统性肾脏和肝脏疾病有关。大多数形式的慢性瘙痒对抗组胺治疗都有抵抗力。迫切需要更好地了解瘙痒的机制，以确定开发新的止痒治疗的细胞靶点。我们提出了一个区分瘙痒和疼痛的啮齿动物模型。瘙痒通常是通过对大鼠或小鼠颈部颈部应用瘙痒介质的部位进行后肢抓挠来评估的。然而，由于生物力学的限制，动物唯一可用的反应是将后肢直接移动到刺激部位。因此，这种方法的一个缺点是，除了瘙痒之外，其他感官特性可能会引起抓挠。在一个涉及脸颊刺激的新模型中，至少有两种运动反应可用：后肢抓挠和前肢擦拭刺激部位。皮内注射组胺对人类来说很痒，几乎只会引起大鼠和小鼠的后肢抓挠。相比之下，令人痛苦的辣椒素几乎只会引起同侧前肢的擦拭。我们建议严格测试这些不同的反应是否区分瘙痒和疼痛，并研究这些感觉特性的神经处理。因此，特殊目标1将测试各种产生瘙痒的化学物质是否选择性地引起后肢的面部抓挠，以及各种产生疼痛的化学物质是否选择性地引起面部前肢的擦拭。这个目标还将测试是否可以通过阻断5-阿片受体的药物来减少抓挠，但不能通过吗啡来减少抓挠，以及是否可以通过阻断5-阿片受体的药物来减少擦伤。具体目标2将通过记录三叉神经细胞对面部皮肤感受野传递的瘙痒和疼痛刺激的反应来研究潜在的神经机制。我们将测试一个假设，即瘙痒信号神经元在与面部抓挠行为相匹配的时间过程中对瘙痒化学物质做出反应。最后，《特定目标3》将利用这一模型来研究面部皮肤干燥引起的慢性瘙痒条件下瘙痒信号通路的敏化。我们将测试这一假设，即瘙痒的化学物质将引起更大的抓挠，而引起疼痛的化学物质将引起抓挠而不是擦拭，这是由于在敏化的瘙痒信号通路中从疼痛到瘙痒的模式转换。对面部瘙痒和疼痛机制的更好理解将为开发阻断瘙痒和疼痛传递的方法提供靶点，具有极大的潜力转化为这些常见疾病的临床治疗。 公共卫生相关性：慢性瘙痒是一个重要的临床问题，与许多皮肤病和全身疾病有关，通常对抗组胺药物治疗耐药。这个项目将研究一种区分面部瘙痒和疼痛的啮齿动物模型，并将解决潜在的神经机制。该项目将提高我们对瘙痒机制的理解，并为治疗瘙痒和疼痛的新疗法的翻译开发确定细胞靶点。

DESCRIPTION (provided by applicant): Chronic itch is a significant clinical problem associated with many dermatological conditions and systemic kidney and liver disease. Most forms of chronic itch are resistant to antihistamine treatment. A better understanding of itch mechanisms is urgently needed to identify cellular targets for development of novel anti-itch treatments. We propose a rodent model that distinguishes between itch and pain. Itch is usually assessed by hindlimb scratching directed toward a site of application of itch mediators in the nape of the neck of rats or mice. However, because of biomechanical limitations, the only response available to the animal is directed movement of the hindlimb to the stimulus site. Therefore, a drawback of the method is that other sensory qualities besides itch are likely to elicit scratching. In a new model involving stimulation of the cheek, at least two motor responses are available: hindlimb scratches and forelimb wipes directed to the stimulus site. Intradermal cheek injection of histamine, which is itchy to humans, elicits almost exclusively hindlimb scratching in rats and mice. In contrast, capsaicin, which is painful, elicits almost exclusively ipsilateral forelimb wiping. We propose to rigorously test if these distinct responses distinguish between itch and pain, and to investigate the neural processing of these sensory qualities. Thus, specific aim 1 will test if a variety of itch-producing chemicals selectively elicit facial scratching with the hindlimb, and if various pain-producing chemicals selectively elicit facial wiping with the forelimb. This aim will also test if scratching is reduced by drugs that block 5-opioid receptors but not by morphine, and if wiping is reduced by morphine but not by drugs blocking 5-opioid receptors. Specific aim 2 will investigate underlying neural mechanisms by recording responses of second-order trigeminal neurons to itch- and pain-evoking stimuli delivered the facial skin receptive field. We will test the hypothesis that itch- signaling neurons respond to itchy chemicals over a time course matching that of facial scratching behavior. Finally, specific aim 3 will exploit this model to investigate sensitization of itch-signaling pathways under conditions of chronic itch produced by dry facial skin. We will test the hypothesis that itchy chemicals will elicit greater scratching, while pain-evoking chemicals will elicit scratching instead of wiping due to a modality switch from pain to itch in sensitized itch-signaling pathways. An improved understanding of facial itch and pain mechanisms will provide targets for the development of means to interrupt itch and pain transmission, with great potential for translation to clinical treatment of these common conditions. PUBLIC HEALTH RELEVANCE: Chronic itch is a significant clinical problem associated with many dermatological conditions and systemic diseases, and is usually resistant to antihistamine treatment. This project will investigate a rodent model that distinguishes between facial itch and pain, and will address the underlying neural mechanisms. The project will improve our understanding of itch mechanisms and identify cellular targets for translational development of new treatments for itch and pain.