Neurite density in skin as a marker for neuropathic pain

描述（由申请人提供）：慢性疼痛已被公认为是一个服务不足的医学领域。临床护理和研究由于缺乏与疼痛的主观主诉的客观相关性而受到阻碍。这对于神经性疼痛患者尤其是一个问题，其中疼痛是由疼痛感测神经元的功能障碍引起的，而不是对感觉到疼痛的区域的损伤。 在这个翻译项目中，我们将评估两种类型的神经损伤的客观证据，看看它们是否与疼痛的投诉。我们将研究这些方法在患有两种常见神经性疼痛疾病之一的成人中的有用性，带状疱疹（带状疱疹）后的带状疱疹后神经痛（PHN），或糖尿病小腿疼痛性神经病变，以及这些疾病的大鼠模型。将比较有和没有疼痛的个体的数据。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，预测谁有或没有带状疱疹或糖尿病疼痛。我们也将评估一项新技术的有用性，即计算小皮肤穿刺活检的皮层内疼痛感觉（伤害感受）神经末梢的密度。 令人惊讶的是，我们小组和其他人的工作表明，神经性疼痛患者在疼痛的皮肤中通常具有较少的伤害性神经末梢。当来自外周的信号量减少时，大脑和脊髓中处理疼痛的神经元就会变得异常活跃。在没有组织损伤的情况下，结果可能是疼痛。这与耳鸣（耳鸣）的发展类似，当人们失去听力时。我们的数据表明，带状疱疹后，PEN疼痛只感觉到那些患者的伤害性神经末梢的密度已降低到低于阈值（650神经突/平方毫米皮肤表面积）。 在特定目标I中，我们将对带状疱疹发作后约6周的患者进行定量感觉测试和皮肤活检，并在6个月后重复这些测试。我们将评估第一组测试的数据或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标记。在具体目标II中，我们将比较正常人和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有疼痛和没有疼痛的个体之间存在阈值，以及我们是否可以识别症状前状态。在特定目标III中，我们计划评估坐骨神经损伤后疼痛大鼠模型中的爪感觉功能。在处死时，将从大鼠爪的底部以及从损伤的神经获取活组织检查，以观察足部中伤害感受神经末梢的密度的变化是否与神经损伤的严重程度以及感觉测试期间大鼠的行为相关。 这项研究的目的是改善慢性神经性疼痛患者的医疗护理，并通过鉴定可用作神经性疼痛存在的替代措施的“生物标志物”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.