Trigeminal Mechanisms of Oral Irritation

描述（由申请人提供）：本提案的总体目标是研究食品、饮料和其他消费品中常见刺激性化学物质产生口腔刺激的神经机制。一项多学科的实验方法将解决啮齿动物模型中三叉神经疼痛通路中的神经元以与人类感知相关的方式发出口腔刺激信号的假设。具体目标如下。具体目标研究不同刺激性化学物质在人类受试者中引起的不同感觉模式。重复或持续口服某些刺激物（辣椒素，浓缩NaC1）引起刺激，刺激强度逐渐增加（致敏），而其他刺激物（尼古丁薄荷醇）引起的刺激减弱（脱敏）。我们将研究额外的刺激性化学物质（酸、芥末油、二氧化碳）是否可以归类为致敏性或脱敏性。我们还将研究刺激物之间的相互作用（例如，交叉脱敏），以及人类是否能够独立于味觉或嗅觉线索定性地区分刺激物。具体目标2。目的：通过记录大鼠尾侧亚核（Vc）单个痛觉神经元对刺激物的反应，探讨口腔刺激的神经机制。我们将确定刺激物诱发的Vc神经元放电模式是否与人类感官评分模式相关。辣椒素和其他致敏剂预计会导致放电逐渐增加，而尼古丁和其他致敏剂预计会导致放电逐渐减少。其他目标是测试是否存在“化学选择性”Vc神经元，以及Vc中的中间神经元和上升投射神经元是否具有相似或不同的性质。具体目标3。通过确定特定拮抗剂是否减少化学诱发的刺激感觉或Vc神经元的激活，研究转导机制。我们将重点关注神经元烟碱受体、酰胺敏感离子通道、香草素受体（VR-1）和Na-/H-膜交换泵。Vc活性将通过单单元记录和c雾免疫组织化学测量。具体目标开发口腔刺激的啮齿动物模型，使用配对偏好范式来测量水与辣椒素水溶液的消耗。我们假设可检测到的辣椒素浓度将被拒绝。该模型将用于研究神经肽P物质在口腔刺激中的作用。5.具体目标为了验证口腔内刺激物降低人类对味觉质量强度的判断，使用了一个敏感的2-alternative强迫选择范式。在一项相应的动物研究中，我们将确定味觉中继NTS （n. tractus solitarius）神经元的反应是否因口服辣椒素而降低

DESCRIPTION (provided by applicant): The overall goal of this proposal is to investigate the neural mechanisms underlying oral irritation produced by common irritant chemicals in foods, beverages and other consumer products. A multidisciplinary experimental approach will address the hypothesis that neurons in the trigeminal pain pathway in a rodent model signal oral irritation in a manner that correlates with human perception. Specific aims are as follows. Specific Aim 1. To investigate the distinct patterns of sensation elicited by different irritant chemicals in human subjects. Repetitive or continual intraoral application of certain irritants (capsaicin, concentrated NaC1) elicits irritation that progressively increases in intensity (sensitization), while irritation elicited by other irritants (nicotine menthol) declines (desensitization). We will study if additional irritant chemicals (acids, mustard oil, CO2) can be categorized as sensitizing or desensitizing. We will also investigate interactions between irritants (e.g., cross-desensitization), and if humans can qualitatively discriminate between irritants independent of taste or smell cues. Specific Aim 2. To investigate neural mechanisms of oral irritation, by recording responses of single nociceptive neurons in subnucleus caudalis (Vc) to lingual application of irritant chemicals in rats. We will determine if the irritant-evoked Vc neuronal firing pattern correlates with the pattern of human sensory ratings. Capsaicin and other sensitizing agents are predicted to elicit a progressive increase in firing, while a progressive decline in firing is predicted for nicotine and other desensitizing agents. Additional goals are to test if "chemo- selective" Vc neurons exist, and if interneurons and ascending projection neurons in Vc have similar or different properties. Specific Aim 3. To investigate transduction mechanisms, by determining if chemically-evoked irritant sensation, or activation of Vc neurons, is reduced by specific antagonists. We will focus on neuronal nicotinic receptors, amiloride-sensitive ion channels, vanilloid (VR-1) receptors, and the Na-/H- membrane exchange pump. Vc activity will be measured by single-unit recording and by c-fog immunohistochemistry. Specific Aim 4. To develop a rodent model of oral irritation, using a paired preference paradigm to measure consumption of water vs. an aqueous solution of capsaicin. We hypothesize that detectable concentrations of capsaicin will be rejected. This model will be used to investigate the role of the neuropeptide, substance P, in oral irritation. Specific Aim 5. To test the hypothesis that intraoral irritants reduce human judgments of the intensity of taste qualities using a sensitive 2-alternative forced-choice paradigm. In a corresponding animal study, we will determine if responses of neurons in the n. tractus solitarius (NTS), a taste relay, are reduced by intraoral capsaicin