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.]]
Common complex persistent pain conditions, such as fibromyalgia and temporomandibular disorder, constitute one of our nation's most significant healthcare problems, yet are ineffectively treated because the underlying molecular mechanisms remain largely unknown. [[We hypothesize that these conditions are driven by abnormalities in catecholamine physiology that result in increased activation of propain molecules and pathways by way of beta2- and beta3-adrenergic receptors.]] Therefore, this proposal applies diverse methodologies in a new clinically-relevant animal model in order to 1) characterize the role of beta-adrenergic systems in mediating persistent pain and 2) identify previously unexploited targets (e.g., beta2- and beta3-adrenergic receptors) for the development of effective therapies for patients with persistent pain conditions.
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