Neurite density in skin as a marker for neuropathic pain

描述(由申请人提供)：慢性疼痛已被认为是一个不充分的医学领域。由于缺乏主观疼痛主诉的客观相关性，临床护理和研究受到阻碍。对于神经性疼痛患者来说，这尤其是一个问题，因为疼痛是由痛觉神经元的故障引起的，而不是感受到疼痛的区域的损伤。 在这个翻译项目中，我们将评估两种神经损伤的客观证据，看看它们是否与疼痛的主诉相关。我们将研究这些方法在患有两种常见神经性疼痛情况之一的成人以及这些情况的大鼠模型中的有效性。带状疱疹后带状疱疹后遗神经痛(PHN)或糖尿病引起的小腿痛性神经病变。有疼痛的人和没有疼痛的人的数据将进行比较。我们将评估特定感觉功能测试的有用性，使用标准化的定量感觉刺激来预测谁有或没有带状疱疹或糖尿病带来的疼痛。我们还将评估一项新技术的实用性，即对小皮肤穿孔活检的表皮层内痛觉(伤害性)神经末梢的密度进行计数。 令人惊讶的是，我们团队和其他人的研究表明，神经性疼痛患者疼痛皮肤上的伤害性神经末梢通常较少。当从外周传入的信号量减少时，大脑和脊髓中的疼痛处理神经元就会变得过度活跃。其结果可能是在没有组织损伤的情况下出现疼痛。这类似于当人们失去听力时耳鸣(耳鸣)的发展。我们的数据表明，带状疱疹后，只有那些伤害性神经末梢密度降低到阈值(650个突起/mm2皮肤表面积)以下的患者才能感受到笔痛。 在具体目标I中，我们将在带状疱疹发病后约6周对患者进行定量感觉测试和皮肤活检，并在6个月后重复这些检查。我们将评估第一组测试的数据，或者两次测试之间的变化，是否可以为那些从疼痛中恢复的人提供一个标记。在特定目标II中，我们将比较正常人和有无疼痛的糖尿病患者的感觉测试和皮肤活检数据，看看是否有证据表明存在一个阈值来区分有无疼痛的个体，以及我们是否可以识别出症状前状态。在具体目标III中，我们计划在坐骨神经损伤后疼痛的大鼠模型上评估爪子的感觉功能。在牺牲时，将从大鼠的爪底和受伤的神经中进行活检，以了解脚部伤害性神经末梢密度的变化是否与神经损伤的严重程度相关，以及与大鼠在感官测试中的行为是否相关。 这项研究的目标是改善慢性神经病理性疼痛患者的医疗护理，并通过识别可用作神经病理性疼痛存在的替代措施的“生物标记物”来促进研究。

DESCRIPTION (provided by applicant): Chronic pain has been recognized as an underserved area of medicine. Clinical care and research are hampered by the lack of objective correlates for the subjective complaint of pain. This is especially a problem for neuropathic pain patients, where the pain is caused by malfunction of the pain-sensing neurons, rather than injury to the area where the pain is felt. In this translational project we will evaluate two types of objective evidence of neural damage to see whether they correlate with the complaint of pain. We will investigate the usefulness of these methods in adults with one of two common neuropathic pain conditions, postherpetic neuralgia (PHN) after shingles (herpes zoster), or painful neuropathy in the lower legs from diabetes mellitus, and in rat models of these conditions. Data from individuals with and without pain will be compared. We will evaluate the usefulness of tests of specific sensory functions, using standardized quantitative sensory stimuli, for predicting who does or does not have pain from shingles or diabetes. We will also evaluate the usefulness of a new technique, counting the density of pain-sensing (nociceptive) nerve endings within the epiderrnal layer of small skin punch biopsies. Surprisingly, work by our group and others show that neuropathic pain patients usually have fewer nociceptive nerve endings in painful skin. When the amount of signal coming in from the periphery decreases, pain-processing neurons in the brain and spinal cord become hyperactive. The result can be pain in the absence of tissue injury. This is similar to the development of tinnitus (ringing in the ears) when people lose hearing. Our data suggests that after shingles, PEN pain is felt by only those patients whose density of nociceptive nerve endings has been reduced below a threshold value (650 neurites/mm2 skin surface area). In Specific Aim I, we will study patients about 6 weeks after onset of shingles with quantitative sensory testing and skin biopsies, and repeat them 6 months later. We will evaluate whether data from the first set of tests, or changes between the two test sessions, can provide a marker for those who recover from pain or not. In Specific Aim II we will compare sensory testing and skin biopsy data from normal people and diabetics with and without pain to see whether there is evidence for a threshold value separating individuals with and without pain, and whether we can identify a presymptomatic state. In Specific Aim III, we plan to evaluate sensory function of the paw in rat models of pain after sciatic nerve injury. At sacrifice, biopsies will be taken from the bottom of the rat's paws as well as from the injured nerves to see whether changes in the density of nociceptive nerve endings in the foot correlate with severity of damage in the nerve and with the rat's behavior during sensory testing. The goal of this research is to improve medical care for patients with chronic neuropathic pain, and facilitate research by identifying "biomarkers" that can be used as surrogate measures for the presence of neuropathic pain.