Role of Interleukin-1β and Neuroinflammation in the Persistence of Neuropathic Pain

• Author / Creator

  Myung-chul Noh

• Persistent hyperexcitability in the primary sensory afferents contributes substantially to the onset and the maintenance of neuropathic pain. Inteleukin-1β (IL-1β) has been implicated to directly interact with interleukin 1 receptor type I (IL-1RI) expressed in dorsal root ganglion (DRG) neurons to not only modulate ion channel function and excitability in a cell type specific manner, but also modify gene expressions to trigger a ‘phenotypic switch’. This thesis aims to illuminate the role of IL-1β in the persistent DRG neuron hyperexcitability and the maintenance of neuropathic pain.
  To do so, we examined the consequences of chronic IL-1β exposure and neuroinflammation, which occur in various animal models of neuropathic pain, on DRG neuron excitability as well as mechanical allodynia. Whole-cell patch clamp analysis of the effects and reversibility of chronic 5-6 day IL-1β exposure was examined in male rat, neuron-enriched DRG cultures as well as in acutely dissociated female mice DRG neuron culture to induction of autoimmune encephalomyelitis (EAE). Furthermore, differential reversibility of mechanical allodynia (pain due to innocuous stimuli) seen in spared nerve injury (SNI) and chronic constriction injury (CCI) models of neuropathic pain was examined in the context of degree and duration of neuroinflammation in the DRG.
  Through the experiments done in this thesis, I illustrated potential IL-1β mediated mechanisms that work in parallel to promote persistent DRG neuron hyperexcitability as well as mechanical allodynia in animal models of neuropathic pain and potentially in humans. I demonstrated 5-6 day 100 pM IL-1β treatment with 50 ng/ml glial cell line derived neurotrophic factor (GDNF) supplementation leads to enduring increase in the action potential duration (AP) in small IB4+
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  DRG neurons, which was largely mediated through decrease in Ca2+-activated K+ conductance (gK,Ca), particularly large conductance BK(Ca) channels. Furthermore, by using acutely dissociated female mice DRG cultures, we showed medium-large (≥26 μm) likely myelinated DRG neurons from EAE mice exhibited increased likelihood of AP discharge, number of AP discharges, and firing frequency in comparison to DRG neurons from CFA control mice. In stark contrast, induction of EAE did not affect small (<26 μm) presumptive unmyelinated DRG neuron excitability. Remarkably, the increase in excitability in medium-large myelinated DRG neurons persisted until 7 days post-onset, when no substantial immune cells and IL-1β expression could be detected in the DRG. Finally, I showed persistent expression of cellular sources of IL-1β, such as activated satellite glial cells and macrophages, correlate with ongoing production of colony stimulating factor 1 (CSF1) as well as mechanical allodynia. Only SNI operated rats, which exhibit persistent mechanical allodynia, displayed persistent neuroinflammation and CSF1 production in the DRGs as opposed to CCI operated animals. This implied ongoing peripheral neuroinflammation mediated by IL-1β as well as other inflammatory mediators may not only promote hyperexcitability in the DRG neurons, but it may also trigger de novo induction of critical mediators such as CSF1.
  The work from this thesis provides additional support to growing evidence that neuropathic pain, sometimes referred to as the “disease of pain,” is a ‘neuroimmune disorder.’ The data obtained in this thesis provide potential mechanisms that neuron-immune crosstalk may facilitate persistent hyperexcitability in the primary afferents and in the DRG, which in turn can indirectly contribute to the onset and the maintenance of central sensitization and neuropathic pain.

• Subjects / Keywords

  • inflammation
  • interleukin 1 beta
  • dorsal root ganglion
  • allodynia
  • chronic pain
  • electrophysiology
  • Neuropathic pain

• Graduation date

  Fall 2019

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-wm52-6q80

• License

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