Rodent model to distinguish between facial itch and pain

区分面部瘙痒和疼痛的啮齿动物模型

• 批准号: 8112494
• 负责人: EARL E CARSTENS
• 金额: $ 15.2万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-16 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8112494
• 关键词: Address; Afferent Neurons; Agonist; Animals; Antihistamines; Antipruritics; Area; Behavior; Biomechanics; Capsaicin; Cheek structure; Chemicals; Chronic; Clinical; Clinical Treatment; Development; Dose; Exhibits; Face; Forelimb; Formalin; Hindlimb; Histamine; Human; Injection of therapeutic agent; Ipsilateral; Kidney Diseases; Liver diseases; Mediator of activation protein; Methods; Microinjections; Modality; Modeling; Morphine; Motor; Movement; Mus; Narcotic Antagonists; Neck; Neurons; Opioid Receptor; PAR-2 Receptor; Pain; Pharmaceutical Preparations; Process; Rattus; Resistance; Rodent Model; Sensory; Sensory Process; Serotonin; Signal Pathway; Signal Transduction; Site; Skin; Stimulus; Systemic disease; Testing; Time; Topical application; Translations; Trigeminal System; cellular targeting; improved; in vivo; mustard oil; neuromechanism; novel; public health relevance; receptive field; relating to nervous system; response; transmission process

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.

描述（由申请人提供）：慢性瘙痒是与许多皮肤病和全身性肾脏和肝脏疾病相关的重要临床问题。大多数形式的慢性瘙痒对抗组胺治疗有抗性。迫切需要更好地了解瘙痒机制，以确定新的抗痒治疗的细胞靶点。我们提出了一个啮齿动物模型来区分痒和痛。瘙痒通常通过对大鼠或小鼠颈后的瘙痒介质应用部位的后肢搔抓来评估。然而，由于生物力学的限制，动物唯一可用的反应是后肢向刺激部位的定向运动。因此，该方法的一个缺点是，除了痒之外，其他感官品质也可能引起抓挠。在一个涉及脸颊刺激的新模型中，至少有两种运动反应是可用的：针对刺激部位的后肢划伤和前肢擦拭。皮肤内注射组胺对人类来说很痒，在大鼠和小鼠身上几乎只会引起后肢抓痒。相比之下，辣椒素会引起疼痛，几乎只会引起同侧前肢擦拭。我们建议严格测试这些不同的反应是否区分瘙痒和疼痛，并研究这些感觉品质的神经处理。因此，特定目标1将测试是否各种产生瘙痒的化学物质选择性地引起后肢的面部抓挠，以及是否各种产生疼痛的化学物质选择性地引起前肢的面部擦拭。这一目的还将测试阻断5-阿片受体的药物是否会减少抓挠而不是吗啡，以及吗啡是否会减少擦拭而阻断5-阿片受体的药物是否会减少擦拭。具体目标2将通过记录二级三叉神经元对传递到面部皮肤感受野的瘙痒和疼痛刺激的反应来研究潜在的神经机制。我们将测试瘙痒信号神经元对瘙痒化学物质的反应与面部抓挠行为的时间过程相匹配的假设。最后，具体目标3将利用该模型来研究由面部皮肤干燥引起的慢性瘙痒条件下瘙痒信号通路的致敏性。我们将测试一个假设，即发痒的化学物质会引起更大的抓挠，而引起疼痛的化学物质会引起抓挠而不是擦拭，因为在致敏的瘙痒信号通路中，从疼痛到瘙痒的模式转换。改善对面部瘙痒和疼痛机制的理解将为开发阻断瘙痒和疼痛传播的手段提供目标，并具有很大的潜力转化为这些常见疾病的临床治疗。