Analgesic Mechanisms In Patients With Chronic Pain

慢性疼痛患者的镇痛机制

• 批准号: 6966395
• 负责人: MITCHELL B MAX
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6966395
• 关键词: analgesics; chronic pain; clinical trials; cytokine; genetic polymorphism; genetic susceptibility; human subject; longitudinal human study; nucleic acid purification; patient oriented research; sciatica

The purpose of this project is to elucidate the mechanisms and principles of prevention and treatment of chronic pain syndromes. Our main current focus is the examination of pain candidate genes in cohorts of pain patients and controls. This year we collected DNA from 314 patients with pain from herniated lumbar disc compressing the nerve root who had been closely followed for 10 years in the Maine Lumbar Spine Study. We chose 20 candidate genes from the pain neuroscience literature by a process that can be applied to any area for initial association studies: We compiled a list of about 200 putative pain-mediating molecules by searching recent pain research abstracts, review articles, and textbooks. We then searched PubMed for each molecule, using the terms ?[molecule] and human and polymorphism? and rated each polymorphism of the molecule on a 0-3 point scale for (1) strength of evidence for involvement in pain processing, particularly for persistent pain after nerve injury; (2) population frequency; and (3) strength of clinical or in vitro evidence that the polymorphism changes function. The highest scoring 20 candidate genes included polymorphisms of genes for cytokine genes and their receptors, pain-related excitatory and inhibitory neurotransmitters and receptors, and growth factors. We then prepared dense haplotype assays for these genes. Our preliminary findings are that patients who carry an interleukin-1 beta polymorphism associated with hypersecretion of that inflammatory cytokine, which had been our highest priority candidate gene, are significantly more likely to have persistent pain in the two years after spine surgery. We have also found that a polymorphism that decreases secretion of the anti-inflammatory cytokine IL-13 is also associated with greater risk of persistent post-surgical sciatica. We are exploring this finding with additional genotyping and haplotype analysis and in vitro cell function studies of the polymorphisms associated with greater pain. We are also exploring genetic risk factors for temporomandibular pain in a longitudinal study of 220 normal women in collaboration with Luda Diatchenko and William Maixner at the University of North Carolina Dental School. We identified three genetic variants (haplotypes) of COMT that we designated as low pain sensitive (LPS), average pain sensitive (APS), and high pain sensitive (HPS) that account for 11% of variability in pain perception. The presence of even a single LPS haplotype diminishes, by as much as 2.3 times, the risk of developing myogenous temporomandibular joint disorder (TMD), a common musculoskeletal pain condition. The LPS haplotype produces much higher levels of COMT enzymatic activity compared to the APS or HPS haplotypes. Thus, three major haplotypes determine the levels of COMT activity that inversely correlate with pain sensitivity and the risk of developing TMD, and possibly other related chronic pain conditions. This is the first study that has identified a genetic polymorphism associated with the risk of developing a chronic pain condition. In a collaborative study with NIMH and Howard University, we showed that a common deletion in the alpha-2C adrenergic receptor is associated with excessive release of the catecholamines norarenaline and adrenaline, which may account for some of the higher risk of hypertension, congestive heart failure, and depression in African-Americans. Twenty-nine healthy African-Americans genotyped for alpha-2 adrenergic receptor subtype polymorphisms underwent tritiated-noradrenaline and adrenaline intravenous infusion and arterial blood sampling for measurements of rates of entry of endogenous noradrenaline and adrenaline into arterial plasma (total body spillovers) by the tracer dilution technique. Eleven subjects were homozygotes for the alpha 2C deletion polymorphism, 9 intravenous infusion of the alpha-2-adrenergic receptorr antagonnist, yohimbine. Administration of yohimbine produced larger, more sustained increments in noradrenaline spillover, heart rate, and anxiety in homozygotes for the receptor molecule deletion than in the other groups. In another study in Caucasians, we and our NIMH collaborators observed an association of this same common deletion in the alpha 2C adrenergic receptor gene with the occurrence of recurrent depression. In other studies, we delineated the haplotype block structure of our 25 pain candidate genes in Caucasian, African-American, and American Indian populations. We are also continuing clinical trials of single drugs, drug combinations, and alternative medicine techniques in chronic lumbar radiculopathy pain; and with NCCAM?s Suzan Khoromi and Marc Blackman have initiated studies of the effects of chronic pain, opioid therapy, and placebo treatment upon endocrine function. An interesting interim result is that in the first 10 patients completing a four-period crossover study, a combination of nortriptyline and morphine, titrated to dose-limiting side effects, provides more pain relief than either single treatment alone. If confirmed by the outcomes of the 35 other patients still in treatment, this will be one of the first studies suggesting one can exceed the current ?barrier? of a mean of 30% pain relief seen with single agents in pain from nerve injury.

该项目的目的是阐明慢性疼痛综合征的预防和治疗的机制和原理。 我们目前的主要重点是检查疼痛患者和对照组中疼痛候选基因的检查。今年，我们从314例患者中收集了颅腰椎间盘疼痛的DNA，这些DNA在缅因州腰椎研究中紧随其后10年的神经根。我们通过一个可以应用于任何领域进行初始关联研究的过程中从疼痛神经科学文献中选择了20个候选基因：我们通过搜索最近的疼痛研究摘要，评论文章和教科书来汇编约200个假定的疼痛疼痛分子列表。然后，我们使用术语？[分子]以及人类和多态性搜索了每个分子的PubMed？并将分子的每种多态性评分为0-3点尺度，以（1）参与疼痛处理的证据强度，尤其是在神经损伤后持续疼痛的情况下； （2）人口频率； （3）临床或体外证据的强度表明多态性变化作用。得分最高的20个候选基因包括细胞因子基因及其受体基因的多态性，与疼痛相关的兴奋性和抑制性神经递质和受体以及生长因子。然后，我们为这些基因制备了致密的单倍型测定。我们的初步发现是，携带白介素-1β多态性的患者与炎性细胞因子的过度分泌有关，这是我们优先候选基因的最高优先候选基因，在脊柱手术后两年中持续疼痛的可能性更大。我们还发现，降低抗炎细胞因子IL-13的分泌的多态性也与持续性后手术坐骨神经痛的风险更大有关。我们正在通过其他基因分型和单倍型分析以及与更大疼痛相关的多态性的体外细胞功能研究来探索这一发现。 我们还在与北卡罗来纳大学牙科学校的Luda Diatchenko和William Maixner合作对220名正常妇女的纵向研究中探索颞下颌疼痛的遗传危险因素。我们确定了COMT的三种遗传变异型（单倍型），我们指定为低疼痛（LPS），平均疼痛敏感（AP）和高疼痛敏感（HPS），占疼痛感知变异性的11％。即使是单个LPS单倍型的存在也会减少多达2.3倍，即产生肌肌肌roti肌肌肌rig骨（TMD）的风险，这是一种常见的肌肉骨骼疼痛疾病。与APS或HPS单倍型相比，LPS单倍型会产生更高水平的COMT酶活性。因此，三种主要的单倍型决定了与疼痛敏感性和发展TMD以及可能其他相关慢性疼痛状况的风险成反比的COMT活性水平。这是第一项确定与发展慢性疼痛疾病风险相关的遗传多态性的研究。 在与NIMH和Howard大学的一项合作研究中，我们表明，Alpha-2C肾上腺素能受体的共同缺失与过度释放儿茶酚胺北烯胺和肾上腺素有关，这可能会导致高血压，充血性心力衰竭，非洲裔美年人抑郁症的较高风险。 29名健康的非洲裔美国人基因分型，用于α-2肾上腺素能受体亚型多态性多态性，经过了杂种甲肾上腺素和肾上腺素静脉输注和动脉血液采样，以测量源自肾上腺素和肾上腺素的肾上腺素质量（总体肾上腺素）的测量。 11名受试者是α2C缺失多态性的纯合子，9个静脉输注α-2-肾上腺素能受体拮抗剂Yohimbine。与其他组相比，Yohimbine的给药在纯合子的去甲肾上腺素溢出，心率和焦虑中产生更大，更持续的增量。在高加索人的另一项研究中，我们和我们的NIMH合作者观察到了α2C肾上腺素能受体基因中这种共同缺失的关联，并发生了复发性抑郁症的发生。在其他研究中，我们描绘了高加索，非裔美国人和美洲印第安人种群中25个疼痛候选基因的单倍型块结构。 我们还在继续进行单一药物，药物组合和替代药物技术的临床试验。随着NCCAM的Suzan Khoromi和Marc Blackman的使用，已经开始研究慢性疼痛，阿片类药物治疗和安慰剂治疗对内分泌功能的影响。一个有趣的临时结果是，在完成四个周期跨界研究的前10名患者中，诺特替林和吗啡的组合（滴定到剂量限制副作用）可提供比单独单独的单一治疗相比，可减轻疼痛。如果通过仍在治疗的35例其他患者的结果确认，这将是最早的研究之一，表明人们可以超过当前的障碍？神经损伤疼痛中的单个药物的平均缓解疼痛的平均值。