Functional pain syndromes affect over 100 million people, yet remain ineffectively treated because the causes are largely unknown. Accumulating evidence suggests that these syndromes are due, in large part, to reduced activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. An estimated 66% of patients with functional pain syndromes, such as fibromyalgia, possess variants in the COMT gene that lead to low activity of the COMT enzyme. Individuals with the ?low COMT activity? genotype report greater pain at baseline and enhanced pain following stressful events that potentiate catecholamine release from sympathetic nerves. Consistent with clinical syndromes, our lab has shown that pharmacologic inhibition of COMT in rodents produces pain at multiple body sites and enhanced pain following repeated stress. In subsequent studies, we demonstrated that COMT-dependent pain is initiated by the peripheral adrenergic receptor ?3 (Adrb3) through the release of pro-inflammatory cytokines (e.g., TNF? and IL-6), and maintained by subsequent increases in TNF? and activation of mitogen activated protein kinases (MAPKs) in spinal cord neurons. Together, these data show that heightened catecholamine tone leads to persistent pain via peripheral Adrb3 and its downstream effectors. In the periphery, Adrb3 is primarily expressed on adipocytes, which are fat cells that surround peripheral nociceptor and sympathetic nerve terminals and control immune responses. Preliminary data reveal that COMT-dependent increases in pro-inflammatory cytokines are mediated by adipocyte Adrb3. Additional data reveal that sustained activation of Adrb3 leads to decreased levels of miR-133a, a microRNA expressed in adipocytes that negatively regulates cytokines and MAPKs. These data indicate that activation of adipocyte Adrb3 may drive chronic COMT-dependent pain via miR-133a-dependent increases in cytokines and MAPKs. However, the direct contribution of adipocyte Adrb3 and miR-133a to pain is not known. Thus, the objective of this proposal is to create unique tools that we can use to define the role of Adrb3 and miR-133a in chronic pain. First, we will generate an inducible adipocyte-specific Adrb3 knockout mouse to determine the contribution of adipocyte Adrb3 to the onset and maintenance of COMT-dependent pain in the absence or presence of stress. Next, we will generate an adipocyte-specific miR-133a viral construct to determine the ability of miR-133a to resolve COMT-dependent pain in the absence or presence of stress. Results from these studies will provide new insights into the peripheral mechanisms that drive chronic pain, and elucidate new targets for the development of peripherally-restricted therapies with improved specificity and side-effect profiles for the treatment of functional pain syndromes.

Public Health Relevance

Common chronic pain syndromes, 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 peripheral Adrb3 and decreased expression of the microRNA miR-133a that regulates pain-relevant genes. Therefore, this proposal will create and characterize an adipocyte-specific Adrb3 knockout mouse and an adipocyte-specific miR-133a construct, which will be unique tools to help us 1) gain new insights into the peripheral mechanisms that drive chronic pain and 2) identify unexploited targets (Adrb3 and miR-133a) for the development of effective peripherally-restricted therapies for patients with chronic pain syndromes.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Research Grants (R03)
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Special Emphasis Panel (ZRG1)
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Oshinsky, Michael L
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Duke University
Schools of Medicine
United States
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Zhang, Xin; Hartung, Jane E; Bortsov, Andrey V et al. (2018) Sustained stimulation of ?2- and ?3-adrenergic receptors leads to persistent functional pain and neuroinflammation. Brain Behav Immun 73:520-532
Kim, Seungtae; Zhang, Xin; O'Buckley, Sandra C et al. (2018) Acupuncture Resolves Persistent Pain and Neuroinflammation in a Mouse Model of Chronic Overlapping Pain Conditions. J Pain 19:1384.e1-1384.e14