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.
Veterans are an especially vulnerable population for experiencing persistent neuropathic pain because of the battlefield injuries which may have a significant adverse impact on quality of life and effective functioning in society. First line therapeutics for neuropathic pain exhibit limited clinical utility and considerable side effects including substance abuse. New targets for the development of well tolerated pain medications that lack abusive qualities are urgently needed. The studies proposed will define the relationship of peripheral nerve injury-induced chemokine signaling in the progression from injury to chronic pain and represent an important step in developing effective treatment for this condition.
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