Work

Mechanisms Underlying Chemokine Signaling-Mediated Hypersensitization of Primary Sensory Neurons in Association with Neuropathic Pain

Public Deposited

Pain normally subserves a vital role in the survival of the organism by prompting the avoidance of situations associated with tissue damage. However, the sensation of pain can become dissociated from its normal physiological role when the pain-sensing nervous system becomes hypersensitive, a condition known as neuropathic pain. Currently available treatment options for neuropathic pain are generally ineffective, but the development of novel therapies is hampered by our incomplete understanding of the underlying mechanisms. Despite its complex pathophysiology, it is clear that neuropathic pain is associated with changes in the excitability of the primary sensory neurons of dorsal root ganglia (DRG), which are caused by long-term changes in gene expression in these neurons. Chemokines are a family of small secreted proteins originally identified by their chemoattractant activity in the immune system. Recent evidence has suggested that upregulated expression of one chemokine, monocyte chemoattractant protein-1 (MCP1, also known as CCL2), and its receptor, CCR2, in DRG neurons may be an important step in generating neuropathic pain. In this thesis, the molecular mechanisms underlying i) neuronal sensitization by activation of CCR2-mediated signaling, and ii) upregulation of MCP1 and CCR2 gene expression in DRG neurons were investigated. To this end, novel transgenic reporter mice were generated in which MCP1 and CCR2 can be simultaneously visualized in vivo. These mice allowed examination of the dynamic changes in cellular localization of active MCP1-CCR2 signaling in neuropathic pain as well as in other neuropathological conditions. The results of this study will provide valuable insights into identification of novel therapeutic targets to treat neuropathic pain.

Last modified
  • 10/08/2018
Creator
DOI
Subject
Keyword
Date created
Resource type
Rights statement

Relationships

Items