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PNAS 102 (12): 4536-4541

Copyright © 2005 by the National Academy of Sciences.

IMMUNOLOGY

A proinflammatory chemokine, CCL3, sensitizes the heat- and capsaicin-gated ion channel TRPV1

Ning Zhang *, Saadet Inan {dagger}, Alan Cowan {dagger}, Ronghua Sun *, Ji Ming Wang *, Thomas J. Rogers {dagger}, Michael Caterina {ddagger}, and Joost J. Oppenheim *, §

*Laboratory of Molecular Immunoregulation, Intramural Research Support Program, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Frederick, MD 21702-1201; {ddagger}Departments of Biological Chemistry and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287; and {dagger}Department of Pharmacology, Fels Institute for Cancer Research and Molecular Biology, Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved February 11, 2005

Received for publication August 17, 2004.

Abstract: Pain, a critical component of host defense, is one hallmark of the inflammatory response. We therefore hypothesized that pain might be exacerbated by proinflammatory chemokines. To test this hypothesis, CCR1 was cotransfected into human embryonic kidney (HEK)293 cells together with transient receptor potential vanilloid 1 (TRPV1), a cation channel required for certain types of thermal hyperalgesia. In these cells, capsaicin and anandamide induced Ca2+ influx mediated by TRPV1. When CCR1:TRPV1/HEK293 cells were pretreated with CCL3, the sensitivity of TRPV1, as indicated by the Ca2+ influx, was increased {approx}3-fold. RT-PCR analysis showed that a spectrum of chemokine and cytokine receptors is expressed in rat dorsal root ganglia (DRG). Immunohistochemical staining of DRG showed that CCR1 is coexpressed with TRPV1 in >85% of small-diameter neurons. CCR1 on DRG neurons was functional, as demonstrated by CCL3-induced Ca2+ ion influx and PKC activation. Pretreatment with CCL3 enhanced the response of DRG neurons to capsaicin or anandamide. This sensitization was inhibited by pertussis toxin, U73122, or chelerythrine chloride, inhibitors of Gi-protein, phospholipase C, and protein kinase C, respectively. Intraplantar injection of mice with CCL3 decreased their hot-plate response latency. That a proinflammatory chemokine, by interacting with its receptor on small-diameter neurons, sensitizes TRPV1 reveals a previously undescribed mechanism of receptor cross-sensitization that may contribute to hyperalgesia during inflammation.

Key Words: CCR1 • chemokine receptor • inflammation • pain

Author contributions: N.Z., S.I, A.C., R.S., T.J.R., M.C., and J.J.O. designed research; N.Z., S.I., A.C., R.S., J.M.W., T.J.R., and M.C. performed research; N.Z., A.C., J.M.W., T.J.R., M.C, and J.J.O. analyzed data; and N.Z., A.C., T.J.R., M.C., and J.J.O. wrote the paper.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: TRPV1, transient receptor potential vanilloid 1; CAP, capsaicin; DRG, dorsal root ganglia; PLC, phospholipase C; Ana, anandamide; PTX, pertussis toxin.

§ To whom correspondence should be addressed. E-mail: oppenhei{at}ncifcrf.gov.

© 2005 by The National Academy of Sciences of the USA

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