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品产生口腔刺激的神经机制。 一个多学科的实验方法将解决的假设，在三叉神经痛通路的啮齿动物模型中的神经元信号口腔刺激的方式，与人类的感知。 具体目标如下。具体目标1。研究不同刺激性化学物质在人体内引起的不同感觉模式。重复或连续口内应用某些刺激物（辣椒素、浓NaCl）会引起刺激，刺激强度逐渐增加（致敏），而其他刺激物（尼古丁、薄荷醇）引起的刺激则会下降（脱敏）。 我们将研究其他刺激性化学物质（酸、芥子油、CO2）是否可归类为致敏或脱敏。 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。通过记录大鼠尾侧亚核（Vc）内单个伤害性神经元对舌刺激性化学物质的反应，探讨口腔刺激的神经机制。 我们将确定刺激诱发的Vc神经元放电模式是否与人类感觉等级的模式相关。 辣椒素和其他致敏剂预计会引起放电的逐渐增加，而尼古丁和其他脱敏剂预计会引起放电的逐渐下降。 另外的目标是测试“化学选择性”Vc神经元是否存在，以及Vc中的中间神经元和上行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。 我们将集中在神经元烟碱受体，阿米洛利敏感的离子通道，香草酸（VR-1）受体，和Na-/H-膜交换泵。 将通过单单位记录和c-fog免疫组织化学来测量Vc活性。具体目标4。建立口腔刺激啮齿动物模型，采用配对偏好范式测量水与辣椒素水溶液的消耗量。 我们假设，可检测浓度的辣椒素将被拒绝。 该模型将用于研究神经肽P物质在口腔刺激中的作用。具体目标5.使用敏感的2-选择强迫选择范式检验口内刺激物降低人对味觉质量强度的判断的假设。 在相应的动物研究中，我们将确定是否神经元的反应。口内辣椒素可减少味觉传递的孤束核（NTS）

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