Chemokine signaling in the transition from acute to chronic pain

Project: Research project

Description

The goal of this proposal is to demonstrate the importance of the chemokine/chemokine
receptor signaling by stromal derived factor 1 alpha (SDF1; also known as CXCL12) and its
cognate receptor CXCR4 in rodent models of neuropathic pain. Dysregulated expression
chemokine receptors have been linked to hyperexcitability of dorsal root ganglia (DRG) neurons
which underlies peripherally-originated neuropathic pain and constitutes a large number of
neuropathic pain disorders. The studies described in this application are designed to fill the gap
in our understanding of how nerve injury-induced excitatory changes in SDF1/CXCR4 signaling
contribute to the persistence of chronic neuropathic pain.
Our preliminary data shows that CXCR4 is absent from sensory neurons in the DRG and are
generally unresponsive to SDF1. Studies in our lab have shown that injury substantially
enhances both levels of CXCR4 transcripts in DRG and sensory neuron expression of CXCR4
in transgenic reporter mice. Further evidence suggests that this injury-mediated modulation of
CXCR4 may also contribute to altered neuronal hyperexcitability. In this proposal, we will carry
out studies of injury-mediated effects on pain thresholds and hyperexcitability at the cellular
level in DRG neurons using the FDA-approved highly specific CXCR4 receptor antagonist to
test the hypotheses that:
i) Block of CXCR4 in DRG neurons derived from injured rodents ameliorates pain behavior;
ii) Injury alters calcium or sodium currents in CXCR4 responsive nociceptive DRG neurons;
iii) Modulation of SDF1/CXCR4 signaling may serve as a molecular switch to a chronic pain
state.
We will also use molecular and immunological methods, and voltage-clamp and current-clamp
recordings to:
iv) Assess injury-mediated effects on altered regulation of expression and modulation of
CXCR4; and
v) Correlate changes at the molecular and cellular levels in injured and adjacent, uninjured DRG
neurons to changes in pain thresholds.
StatusFinished
Effective start/end date1/1/1412/31/17

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

Fingerprint

Spinal Ganglia
Chemokines
Chronic Pain
Neuralgia
Wounds and Injuries
CXCR4 Receptors
Pain Threshold
Neurons
Sensory Receptor Cells
Rodentia
Somatoform Disorders
Transgenic Mice
Sodium
Chemokine Receptors
Calcium
Pain

ASJC

  • Medicine(all)