Persistent COMT-dependent Pain: Role of beta-adrenergic Receptors

持续性 COMT 依赖性疼痛：β-肾上腺素能受体的作用

基本信息

批准号：
8725747
负责人：
Andrea G Nackley
金额：
$ 35.39万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8725747
关键词：
Acute Adrenergic Agents Adrenergic Antagonists Adrenergic Receptor Animal Model Animals Astrocytes Attenuated Automobile Driving Behavioral Brain region Carrageenan Catechol O-Methyltransferase Catecholamines Cells Cerebrospinal Fluid Characteristics Complex Data Depressed mood Development Dose Enzymes Epinephrine Exhibits Fibromyalgia Gene Expression Genetic Healthcare Interleukin-1 Interleukin-12 Interleukin-6 Knockout Mice Location Maps Measures Mechanics Mediating Methodology Methods Microglia Modeling Molecular Mus Neuroglia Neurons Nitric Oxide Nociception Onset of illness Outcome Study Pain Pathway interactions Patients Perception Peripheral Persistent pain Physiology Play Production Rattus Risk Role Signaling Molecule Site Spinal Spinal Cord Stimulus System TNF gene Techniques Temporomandibular Joint Disorders Testing Tumor Necrosis Factor-alpha Withdrawal Work adrenergic beta-adrenergic receptor brain tissue clinically relevant cytokine effective therapy genetic variant inhibitor/antagonist insight novel novel strategies pain behavior peripheral blood protein expression research study transmission process

项目摘要

DESCRIPTION (provided by applicant): Complex persistent pain conditions, such as fibromyalgia (FM) and temporomandibular disorder (TMD), are ineffectively treated because the underlying molecular mechanisms remain largely unknown. Work by our group and others suggests that these conditions are due, in large part, to diminished activity of catechol-O- methyltransferase (COMT; an enzyme that metabolizes catecholamines), which results in elevated levels of catecholamines and increased activity of beta2/3-adrenergic receptors (beta2/3ARs). However, the exact mechanisms whereby beta2/3ARs mediate COMT-dependent pain are unclear and necessitate further study. Preliminary data show that activation of beta2/3ARs may increase pain sensitivity by increasing the expression of downstream signaling molecules. We show that COMT inhibition results in increased expression of the proinflammatory cytokines tumor necrosis factor-alpha (TNF1), interleukin-12 (IL-12), and interleukin-6 (IL-6) as well as nitric oxide (NO), and that this increase is blocked by 2AR antagonists. [[Additional data further suggest that COMT- dependent pain is mediated in part by peripheral adrenergic systems as adrenalectomized rats lacking peripheral epinephrine exhibit reduced COMT-dependent pain sensitivity. The present application proposes to extend this work by applying diverse methodologies in a novel animal model of persistent pain produced by sustained COMT inhibition in order to elucidate the role that betaARs play in driving persistent pain at cellular and systems levels. First, we will apply behavioral pharmacologic methods in intact rats, adrenalectomized rats, and COMT knockout mice to determine the site of action whereby beta-adrenergic systems drive persistent COMT-dependent pain. Second, we will apply immunocytochemical techniques to determine the role of betaARs in mediating the activation of neurons, microglia, and astrocytes following sustained COMT inhibition. Third, we will apply molecular biologic methods to determine the role of betaARs in mediating the expression of proinflammatory cytokines and NO following sustained COMT inhibition. We hypothesize that persistent COMT-dependent pain produces long-term changes in cellular activity and expression of proinflammatory cytokines and NO by way of peripheral, spinal, and central beta2/3ARs. The novel approach of these studies will 1) identify the subtype and location of betaARs that contribute to persistent pain conditions such as FM and TMD, 2) characterize the long-term consequences of sustained betaAR activation on neurons and glia located in spinal and brain regions that relay pain information, 3) characterize the long-term consequences of sustained 2AR activation on proinflammatory cytokines and NO, which represent validated markers of nociception, and 4) determine the ability of beta2/3AR antagonists to suppress the transmission of nociceptive information. The outcome of these studies will provide new insights into mechanisms underlying maladaptive pain conditions as well as contribute to the identification of previously unexploited targets (e.g., beta2- and beta3ARs) for development of effective therapies for patients with persistent pain conditions.]]

描述（由申请人提供）：复杂的持续疼痛条件，例如纤维肌痛（FM）和颞下颌疾病（TMD），由于基本的分子机制在很大程度上未知，因此无效治疗。我们小组和其他人的工作表明，这些条件在很大程度上是由于儿茶酚 - 甲基转移酶的活性降低（COMT；一种代谢儿茶酚胺的酶），这会导致儿茶酚胺水平升高，并增加了β2/3-肾上腺素受体的活性（beta2/3-辅助受体（beta2/3ars）。但是，beta2/3ARS介导COMT依赖性疼痛的确切机制尚不清楚，需要进一步研究。初步数据表明，β2/3AR的激活可能通过增加下游信号分子的表达来增加疼痛敏感性。我们表明，COMT抑制作用会导致促炎细胞因子肿瘤坏死因子 - α（TNF1），白介素12（IL-12）和白介素6（IL-6）以及氮氧化物（NO）以及这种增加的增长是由2AR拮抗剂阻挡的。 [进一步的数据进一步表明，由于缺乏外周肾上腺素的肾上腺切除术大鼠表现出降低COMT依赖性疼痛敏感性，因此肾上腺肾上腺素能系统的一部分是由外周肾上腺素能系统介导的。本应用建议通过在持续COMT抑制产生的新型动物模型中应用多种方法来扩展这项工作，以阐明Betaars在驱动细胞和系统水平的持续疼痛方面所起的作用。首先，我们将在完整的大鼠，肾上腺切除大鼠和COMT基因敲除小鼠中应用行为药理方法来确定β-肾上腺素能系统驱动持续性COMT依赖性疼痛的作用部位。其次，我们将采用免疫细胞化学技术来确定βAR在持续COMT抑制后介导神经元，小胶质细胞和星形胶质细胞激活中的作用。第三，我们将采用分子生物学方法来确定βAR在介导促炎细胞因子表达中的作用，并且没有持续的COMT抑制作用。我们假设持续的COMT依赖性疼痛会导致细胞活性和促炎细胞因子的表达的长期变化，而没有外周，脊柱和中央beta2/3ars的方式。 The novel approach of these studies will 1) identify the subtype and location of betaARs that contribute to persistent pain conditions such as FM and TMD, 2) characterize the long-term consequences of sustained betaAR activation on neurons and glia located in spinal and brain regions that relay pain information, 3) characterize the long-term consequences of sustained 2AR activation on proinflammatory cytokines and NO, which represent validated markers of nociception, 4）确定β2/3AR拮抗剂抑制伤害性信息传播的能力。这些研究的结果将为适应不良疼痛条件的机制提供新的见解，并有助于鉴定以前未开发的靶标（例如beta2-和beta3ars），以开发持续性疼痛条件患者的有效疗法。