Chronic orofacial pain: genetics, cognitive-emotional factors, and endogenous modulatory systems

 描述（由申请人提供）：慢性疼痛影响了大量的美国人，估计每年花费6000亿美元。特别是，颞下颌关节紊乱病（TMD），一种受生物，心理，环境和社会因素影响的复杂慢性疼痛状况影响约6%的人口。最近的研究表明，遗传学在疼痛敏感性、调制和慢性疼痛和TMD发展的易感性中起着重要作用。个人慢性疼痛的经历是高度可变的;有些人受到轻度影响，而另一些人则遭受衰弱性功能障碍。个体对治疗干预的反应也有很大差异;对于一些人来说，药物治疗非常有效，而在其他人中，疼痛仅略有减轻。临床疼痛结局中高达50%的变异性已被证明是继发于预期诱导的镇痛，其定义为个体对治疗干预的感知导致的疼痛减轻。换句话说，患者的期望可以调节个体疼痛体验，处理和对疼痛治疗的反应。因此，更好地了解遗传效应对预期诱导的镇痛和激活内源性抑制系统的倾向的变化是优化疼痛治疗的关键。我们开发了一种新的综合性遗传、行为和影像学方法来研究TMD患者预期镇痛的行为、心理和神经机制中遗传变异的作用。我们致力于实现以下具体目标：1.检验候选基因的变异与预期诱导的镇痛相关的假设，预测慢性口面疼痛内表型; 2.检验假设，即个体心理特征是期望引起的镇痛的复杂遗传调节的独特调节剂，而不管疾病的严重程度;和3。检验特定（已识别）基因的变异预测预期诱导的镇痛和前额和边缘区相关神经元变化的假设。所确定的基因型将作为重要的标志物来预测主观（例如疼痛报告）和客观（例如神经元）的预期诱导镇痛反应，同时控制不同个性的调节作用。我们预期：a）提供研究慢性口面疼痛的药物基因组学的新框架，B）鉴定可用于开发新的治疗靶点和策略的遗传标记和机制，以及最终，c）确定哪些患者最有可能对特定治疗作出反应。

 DESCRIPTION (provided by applicant): Chronic pain affects a large number of Americans, costing an estimated $600 billion annually. In particular, temporomandibular joint disorder (TMD), a complex chronic pain condition influenced by biological, psychological, environmental and social factors affects about 6% of the population. Recent studies suggest that genetics plays an important role in pain sensitivity, modulation and susceptibility to the development of chronic pain and TMD. Individual chronic pain experience is highly variable; some people are mildly affected, while others suffer debilitating dysfunction. Individuals also vary substantially n their responses to therapeutic interventions; for some, pharmacological treatments are highly efficacious while in others only modest reductions in pain occur. Up to 50% of the variability in clinical pain outcomes has been shown to be secondary to expectancy-induced analgesia, defined as the reduction in pain in an individual that results from his or her perception of the therapeutic intervention. In other words, patients' expectancies can modulate the individual pain experience, processing and response to pain treatments. Therefore, better understanding of the genetic effects on expectancy-induced analgesia and the variability in proneness to activate endogenous inhibitory systems is critical to optimize pain treatments. We developed a novel comprehensive genetic, behavioral and imaging approach to study the role of genetic variations on behavioral, psychological and neuronal mechanisms of expectancy-induced analgesia in patients with TMD. We address the following specific aims: 1. Test the hypothesis that variants in candidate genes are associated with expectancy-induced analgesia predicting chronic orofacial pain endophenotypes; 2. Test the hypothesis that individual psychological traits are unique modulators of the complex genetic moderation of expectancy-induced analgesia, regardless of the severity of the disease; and 3. Test the hypothesis that variations in the specific (identified) genes predict expectancy-induced analgesia and related neuronal changes in the prefrontal and limbic areas. The identified genotypes will serve as important markers to predict subjective (e.g. pain reports) and objective (e.g. neuronal) responses to expectancy-induced analgesia while controlling for modulatory effects of distinct personalities. We anticipate: a) to provide a new framework to study the pharmacogenomics of chronic orofacial pain, b) to identify genetic markers and mechanisms that can be used to develop new therapeutic targets and strategies and ultimately, c) to determine which patients are most likely to respond to specific treatments.