CXCR4 chemokine receptor signaling mediates pain hypersensitivity in association with antiretroviral toxic neuropathy

Sonia K. Bhangoo, Dongjun Ren, Richard J. Miller, David M. Chan, Matthew S. Ripsch, Clarissa Weiss, Christian McGinnis, Fletcher A. White*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

125 Scopus citations


Nucleoside reverse transcriptase inhibitors (NRTIs) are known to produce painful neuropathies and to enhance states of pain hypersensitivity produced by HIV-1 infection. It has also been observed that in some neuropathic pain models, chemokines and their receptors are upregulated, perhaps contributing to the pain state. In order to understand if chemokines are involved in NRTI-mediated sensory neuropathies, we treated rats with the anti-retroviral drug, 2′,3′-dideoxycytidine (ddC), which is known to produce an extended period of hyperalgesia and allodynia. Using in situ hybridization, we observed that under normal conditions, CXCR4 chemokine receptors were widely expressed by satellite glia in the dorsal root ganglia (DRG) and Schwann cells in the sciatic nerve. A limited number of DRG neurons also expressed CXCR4 receptors. The chemokine SDF-1/CXCL12 was similarly expressed in glial cells in the DRG and peripheral nerve. Following a single administration of ddC, expression levels of CXCR4 mRNA in glia and neurons and SDF-1 mRNA in glia increased considerably. The functional nature of increased CXCR4 mRNA expression was confirmed by measuring SDF-1 induced [Ca2+]i increases in acutely isolated DRG neurons and glia. In contrast, the expression of the chemokine receptors CCR2 and CCR5 did not change following ddC treatment. Pain hypersensitivity produced by ddC could be inhibited by treatment with the CXCR4 antagonist, AMD3100. Hence, we postulate that NRTIs produce pain hypersensitivity through the upregulation of CXCR4 signaling in the DRG. Increased numbers of CXCR4 receptors would also explain the synergism observed between NRTI treatment and the proalgesic effects of HIV-1 infection.

Original languageEnglish (US)
Pages (from-to)581-591
Number of pages11
JournalBrain, Behavior, and Immunity
Issue number5
StatePublished - Jul 2007


  • CXCR4
  • Chemokine
  • HIV
  • Neuropathic pain
  • SDF1

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience


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