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Project

Toll-like receptor 4 signaling in chronic neuropathic pain after SCI

Funder: Craig H Neilsen Foundation

Funding period
USD 300 K
Funding amount
Abstract
Chronic neuropathic pain in body regions below the level of spinal cord injury (SCI) (below level neuropathic pain) has a high prevalence, is frequently severe and has debilitating consequences. The mechanisms underlying the development of pain after spinal cord injury are incompletely understood, but microglial / astroglial activation and neuroinflammation significantly contribute to the development of pain. From other models of peripheral neuropathies, there is plenty of evidence that Toll-like receptor 4 (TLR4) and receptor for advanced glycation end-products (RAGE) and one of its ligands, high mobility group protein B1 (HMGB1 = amphotherin) play a major role in the development of pain. HMGB1 is normally a gene-regulatory nuclear protein, which is extracellularly released in the context of cellular stress and is one of several Danger Associated Molecular Patterns (DAMPs; alarmins). HMGB1 is strongly upregulated at the lesion site in rodents with SCI and after spinal ischemia, and acute and long-term increases of HMGB1 are found in serum samples of SCI patients. Its receptors, TLR4 and RAGE are expressed in sensory neurons, microglia and astroglia.To define the role of TLR4 / RAGE / HMGB1 in the development of chronic neuropathic pain after SCI, we will use transgenic mouse models for the cre-dependent, tamoxifen-inducible deletion of TLR4 specifically in primary sensory neurons, astroglia or microglia.In Aim 1), we will analyze changes in pain-like behavior in these mice after a mild contusion SCI compared to sham animals and animals without TLR4 deletion. We will further examine electrophysiological properties of DRG neurons, and neuroinflammatory markers. In Aim 2), we will further analyze the potential role of HMGB1, a known TLR4/RAGE ligand, in sensitizing DRG neurons after SCI and determine whether increases in HMGB1 are found in serum of acute and chronic SCI patients and the potential association with the development of chronic pain. In parallel, potential increases in HMGB1 in serum, CSF and DRGs of mice that have undergone a contusion injury and do or do not develop signs of below level pain will be analyzed. With these aims, we will pursue our main hypothesis that TLR4 activation by HMGB1 in sensory neurons, microglia or astrocytes contributes to the development and maintenance of chronic neuropathic pain after SCI. Taken together, this proposal will generate essential data for subsequent larger follow-up studies to pharmacologically manipulate TLR4/RAGE/HMGB1 signaling in the development and maintenance of SCI pain and to expand the proposed clinical studies. (CHN: SCIRTS chn:wdg)
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System

Categories
  • FOR (ANZSRC)

    1109 Neurosciences

  • RCDC

    Injury (total) Accidents/Adverse Effects

  • RCDC

    Injury - Trauma - (Head and Spine)

  • RCDC

    Neurosciences

  • RCDC

    Pain Research

  • RCDC

    Pain Conditions - Chronic

  • RCDC

    Spinal Cord Injury

  • RCDC

    Neurodegenerative

  • RCDC

    Peripheral Neuropathy

  • HRCS HC

    Neurological

  • HRCS RAC

    2.1 Biological and endogenous factors

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science