Unraveling the Complexities of Idiopathic Pain Disorders: From Mouse to Man Public Deposited

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  • June 7, 2019
Creator
  • Ciszek, Brittney
    • Affiliation: School of Dentistry, Oral and Craniofacial Biomedicine PhD Program
Abstract
  • Idiopathic pain disorders (IPDs) are common in the population, yet poorly understood and managed. It is generally accepted that IPDs result from variability in genetic and environmental factors that impact the expression of pain-relevant genes, such as catechol-O-methyltransferase (COMT; an enzyme that metabolizes catecholamines). Human genetic variants coding for reduced levels of COMT are associated with increased experimental pain and IPD risk. Preclinical work in our lab has further shown that COMT-dependent pain is mediated via β2- and β3-adrenergic receptors (ARs) and downstream signaling mediators. Emerging evidence also implicates a role for microRNAs, regulators of gene expression, in IPDs and adrenergic signaling. Yet, more work is required to elucidate the contribution of distinct populations of βARs and microRNAs to persistent pain in preclinical and clinical settings. Thus, the present studies aim to 1) determine which βAR-enriched tissues drive COMT-dependent pain and 2) identify specific microRNAs associated with COMT-dependent and idiopathic pain. To identify a site-of-action for COMT-dependent pain, we measured the ability of peripheral, spinal, and supraspinal β2- and β3-AR antagonists to block the development of pain initiated by a COMT inhibitor and to reverse pain established in COMT-/- mice. Peripheral antagonist administration blocked pain produced by COMT pharmacologic inhibition, but not gene knockdown. This suggests that peripherally-located β2- and β3-ARs initiate, but do not maintain COMT-dependent pain. Next, to elucidate the role of microRNAs in persistent pain, we examined whole blood microRNA expression profiles collected from rats receiving the COMT inhibitor or from patients with IPDs. Results demonstrated that COMT-dependent pain and IPDs are each associated with significant microRNA dysregulation. Clinical results further demonstrated that microRNA expression profiles differentiate IPD patients into two subtypes with distinct pain phenotypes, psychological characteristics, and biological correlates. Collectively, the results presented in these studies suggest that βARs and microRNAs represent novel targets for the treatment of idiopathic pain. Peripherally-acting βAR antagonists may be beneficial in acute clinical settings to prevent the development of idiopathic pain among susceptible individuals. MicroRNAs and/or microRNA inhibitors may also represent novel treatments for established pain as well as to diagnose and differentiate IPD subtypes.
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Rights statement
  • In Copyright
Advisor
  • Khan, Asma
  • Maixner, William
  • Sethupathy, Praveen
  • Nackley, Andrea
  • Slade, Gary
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
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