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: 7970969
• 负责人: EARL E CARSTENS
• 金额: $ 19.07万
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7970969
• 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; 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; Serotonin Agonists; 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学疾病以及全身性肾脏和肝病有关的重大临床问题。大多数形式的慢性瘙痒对抗组胺药的抗性。迫切需要更好地了解瘙痒机制，以鉴定出新的反诉治疗的细胞靶标。我们提出了一个区分瘙痒和疼痛的啮齿动物模型。通常，通过将瘙痒介质在大鼠或小鼠颈部颈颈部应用的部位抓取的后肢刮擦来评估瘙痒。但是，由于生物力学的局限性，动物可用的唯一反应是后肢的导向对刺激部位的运动。因此，该方法的缺点是，除了瘙痒之外，其他感觉品质可能会引起划痕。在涉及刺激脸颊的新模型中，至少有两个电动机反应可用：引导到刺激部位的后肢划痕和前肢湿巾。在人类发痒的组胺内注射皮内颊注射，几乎完全引起大鼠和小鼠的后肢刮擦。相比之下，辣椒素是痛苦的，几乎完全引起了同侧前肢擦拭。我们建议严格测试这些独特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，特定的目标1将测试是否有选择性地引起后肢的面部刮擦，以及是否有选择性地产生疼痛的化学物质，是否有选择地引起前肢擦拭面部擦拭。该目的还将测试是否通过阻断5-阿片受体而不是吗啡的药物减少刮擦，并且如果吗啡会减少擦拭，而不是通过阻断5-阿片类受体的药物减少。特定的目标2将通过记录二阶神经元对瘙痒和疼痛诱发刺激的二阶神经元的反应来研究潜在的神经机制，从而提供了面部皮肤的接受场。我们将检验以下假设：瘙痒信号神经元在时间过程中对瘙痒化学物质响应与面部刮擦行为相匹配的假设。最后，在干燥面部皮肤产生的慢性瘙痒条件下，特定的目标3将利用该模型来研究瘙痒信号途径的敏化。我们将检验以下假设：瘙痒化学物质会引起更大的刮擦，而疼痛引起的化学物质会引起刮擦而不是由于敏感的瘙痒信号途径从疼痛转变为瘙痒而而不是擦拭。对面部瘙痒和疼痛机制的改进理解将为开发中断瘙痒和疼痛传播的方法提供目标，并有很大的潜力转化为对这些常见状况的临床治疗。 公共卫生相关性：慢性瘙痒是与许多皮肤病学疾病和全身性疾病有关的重大临床问题，通常对抗组胺治疗有抵抗力。该项目将研究一个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，并确定细胞靶标，用于转化新疗法的瘙痒和疼痛。