@phdthesis{Leinders2016,
  author    = {Leinders, Mathias},
  title     = {microRNAs in chronic pain},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144395},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2016},
  abstract  = {Chronic pain is a common problem in clinical practice, not well understood clinically, and frequently tough to satisfactorily diagnose. Because the pathophysiology is so complex, finding effective treatments for people with chronic pain has been overall less than successful and typically reduced to an unsatisfactory trial-and-error process, all of which translates into a significant burden to society. Knowledge of the mechanisms underlying the development of chronic pain, and moreover why some patients experience pain and others not, may aid in developing specific treatment regimens. Although nerve injuries are major contributors to pain chronification, they cannot explain the entire phenomenon. Considerable research has underscored the importance of the immune system for the development and maintenance of chronic pain, albeit the exact factors regulating inflammatory reactions remain unclear. Understanding the putative molecular and cellular regulator switches of inflammatory reactions will open novel opportunities for immune modulatory analgesics with putatively higher specificity and less adverse effects. It has become clear that small, non- coding RNA molecules known as microRNAs are in fact potent regulators of many thousands of genes and possibly cross-communicate between cellular pathways in multiple systems acting as so-called "master-switches". Aberrant expression of miRNAs is now implicated in numerous disorders, including nerve injuries as well as in inflammatory processes. Moreover, compelling evidence supports the idea that miRNAs also regulate pain, and in analogy to the oncology field aid in the differential diagnosis of disease subtypes. In fact, first reports describing characteristic miRNA expression profiles in blood or cerebrospinal fluid of patients with distinct pain conditions are starting to emerge, however evidence linking specific miRNA expression profiles to specific pain disorders is still insufficient. The present thesis aimed at first, identifying specific miRNA signatures in two distinct chronic pain conditions, namely peripheral neuropathies of different etiologies and fibromyalgia syndrome. Second, it aimed at identifying miRNA profiles to better understand potential factors that differentiate painful from painless neuropathies and third, study the mechanistic role of miRNAs in the pathophysiology of pain, to pave the way for new druggable targets. Three studies were conducted in order to identify miRNA expression signatures that are characteristic for the given chronic pain disorder. The first study measured expression of miR-21, miR-146a and miR-155 in white blood cells, skin and nerve biopsies of patients with peripheral neuropathies. It shows that peripheral neuropathies of different etiologies are associated with increased peripheral miR-21 and miR-146a, but decreased miR-155 expression. More importantly, it was shown that painful neuropathies have increased sural nerve miR-21 and miR-155 expression, but reduced miR-146a and miR-155 expression in distal skin of painful neuropathies. These results point towards the potential use of miRNAs profiles to stratify painful neuropathies. The seconds study extends these findings and first analyzed the role of miR-132-3p in patients and subsequently in an animal model of neuropathic pain. Interestingly, miR-132-3p was upregulated in white blood cells and sural nerve biopsies of patients with painful neuropathies and in animals after spared nerve injury. Pharmacologically modulating the expression of miR-132-3p dose-dependently reversed pain behavior and pain aversion, indicating the pro-nociceptive effect of miR-132-3p in chronic pain. This study thus demonstrates the potential analgesic impact by modulating miRNA expression. Fibromyalgia is associated with chronic widespread pain and, at least in a subgroup, impairment in small nerve fiber morphology and function. Interestingly, the disease probably comprises subgroups with different underlying pathomechanisms. In accordance with this notion, the third study shows that fibromyalgia is associated with both aberrant white blood cell and cutaneous miRNA expression. Being the first of its kind, this study identified miR-let-7d and its downstream target IGF-1R as potential culprit for impaired small nerve fiber homeostasis in a subset of patients with decreased intra-epidermal nerve fiber density. The work presented in this thesis is a substantial contribution towards the goal of better characterizing chronic pain based on miRNA expression signatures and thus pave the way for new druggable targets.},
  subject      = {miRNS},
  language  = {en}
}