Contribution of ADA1A polymorphism to persistent pain states

描述（由申请人提供）：数百万美国人患有无法缓解的持续性疼痛，这对他们的生活质量造成了毁灭性的影响，并严重负担了我们的医疗保健系统。越来越多的证据表明，顽固性疼痛经常与焦虑、抑郁和其他心理特征共病，通常表现为过敏障碍，其中疼痛的潜在物理基础是未知的。认知和情感风险因素在这些特发性疼痛状况发展中的作用尚未得到充分探讨。对于特发性疾病，如纤维肌痛、肠易激综合征和颞下颌关节疾病（TMD）的发展，一个令人信服的解释是肾上腺素能神经递质系统的失调。一些编码肾上腺素能受体的基因的多态性变异已被证明可增加发生TMD的风险；这些基因也与消极情绪和认知影响有关。本研究将利用遗传技术和小鼠行为模型研究α -肾上腺素能受体（ADRA）基因多态性与慢性疼痛危险因素之间的关系。我们对一项小型前瞻性队列的初步研究显示，ADRA1A基因变异与TMD发展风险之间存在密切联系。在这里，我们想采用一个新的病例对照研究人群来验证和扩展这些初步发现。为了确认α -肾上腺素能受体对体内疼痛敏感性和情感状态的贡献，我们将使用小鼠炎症性疼痛和行为模型。为了研究观察到的关联的潜在分子机制，将研究从参与研究的每个受试者收集的白细胞样本中ADRA1A表达模式的个体差异。这些实验将提供更好的理解肾上腺素能神经调节如何促进病理伤害性和情感状态，最终导致持续疼痛状况的发展。确定TMD的遗传和环境风险因素将允许开发精确的诊断工具，并为镇痛治疗提供新的靶点。确定持续性疼痛障碍如TMD发展的遗传和环境风险因素对于诊断和治疗这些使人衰弱的疾病至关重要。本研究将探讨慢性疼痛患者TMD的发病原因，并探讨肾上腺素能受体影响疼痛敏感性和负性情绪特征的分子机制。

DESCRIPTION (provided by applicant): Millions of Americans suffer from unrelieved persistent pain, which has a devastating effect on their quality of life and severely burdens our health care system. There is growing evidence that intractable pain is frequently comorbid with anxiety, depression, and other psychological traits, often manifesting as hypersensitivity disorders in which the underlying physical substrate of the pain is unknown. The role of cognitive and affective risk factors in the development of these idiopathic pain conditions has not been adequately explored. A compelling explanation for the development of idiopathic disorders, such as fibromyalgia, irritable bowel syndrome, and temporomandibular joint disease (TMD), is disregulation of the adrenergic neurotransmitter system. Polymorphic variants of several genes encoding adrenergic receptors have been shown to elevate risk for developing TMD; these genes have also been associated with negative mood and cognitive effects. This proposal will investigate the relationship between alpha-adrenergic receptor (ADRA) gene polymorphisms and risk factors for chronic pain using genetic techniques and murine models of behavior. Our preliminary studies with a small prospective cohort showed a strong link between genetic variants of ADRA1A and risk of TMD development. Here we would like to employ a novel case control study population to verify and extend these preliminary findings. To confirm the contribution of alpha-adrenergic receptors to pain sensitivity and affective states in vivo, we will use mouse inflammatory pain and behavioral models. To investigate potential molecular mechanisms underlying the observed associations, individual variations in ADRA1A expression patterns will be studied in white blood cell samples collected from each subject enrolled in the study. These experiments will provide a better understanding of how adrenergic neuromodulation contributes to pathological nociceptive and affective states, ultimately leading to the development of a persistent pain condition. Identifying genetic and environmental risk factors for TMD will allow for the development of precise diagnostic tools, and provide novel targets for analgesic therapies. Determining the genetic and environmental risk factors for the development of persistent pain disorders such as TMD is crucial for diagnosing and treating these debilitating diseases. This proposal will explore the causes of TMD in a population of chronic pain patients, and investigate the molecular mechanisms by which adrenergic receptors contribute to pain sensitivity and negative mood traits.