Contribution of ADA1A polymorphism to persistent pain states

描述(申请人提供)：数以百万计的美国人遭受无法缓解的持续性疼痛，这对他们的生活质量产生了毁灭性的影响，并给我们的医疗保健系统带来了严重负担。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并存，通常表现为超敏反应障碍，其中疼痛的潜在生理基础未知。认知和情感风险因素在这些特发性疼痛条件的发展中的作用还没有得到充分的探讨。对纤维肌痛、肠易激综合征和颞下颌关节病(TMD)等特发性疾病的发展，一个令人信服的解释是肾上腺素能神经递质系统的失调。编码肾上腺素能受体的几个基因的多态变异已被证明会增加患上TMD的风险；这些基因也与负面情绪和认知影响有关。这项建议将利用基因技术和小鼠行为模型来研究α-肾上腺素能受体(ADRA)基因多态与慢性疼痛危险因素的关系。我们对一小部分前瞻性队列进行的初步研究表明，ADRA1A的遗传变异与TMD发生的风险之间存在很强的联系。在这里，我们想要采用一个新的病例对照研究人群来验证和推广这些初步发现。为了证实α-肾上腺素能受体在体内对疼痛敏感性和情感状态的作用，我们将使用小鼠炎症性疼痛和行为模型。为了研究潜在的分子机制，ADRA1A表达模式的个体差异将在从参与研究的每个受试者中收集的白细胞样本中进行研究。这些实验将更好地理解肾上腺素能神经调节如何促进病理性的伤害性和情感状态，最终导致持续性疼痛状况的发展。识别TMD的遗传和环境危险因素将有助于开发精确的诊断工具，并为止痛治疗提供新的靶点。确定导致持续性疼痛障碍(如TMD)的遗传和环境风险因素对于诊断和治疗这些令人衰弱的疾病至关重要。这项建议将探索慢性疼痛患者群体中TMD的原因，并研究肾上腺素能受体促进疼痛敏感性和负面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.