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PNAS 100 (13): 7947-7952

Copyright © 2003 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / NEUROSCIENCE

Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2

Catherine Abbadie*,{dagger}, Jill A. Lindia*, Anne Marie Cumiskey*, Larry B. Peterson*, John S. Mudgett{ddagger}, Ellen K. Bayne{ddagger}, Julie A. DeMartino{ddagger}, D. Euan MacIntyre*, and Michael J. Forrest*

*Departments of Pharmacology and {ddagger}Immunology and Rheumatology, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065

Accepted for publication April 22, 2003.

Received for publication March 7, 2003.

Abstract: Mice lacking the chemokine receptor chemotactic cytokine receptor 2 (CCR2) have a marked attenuation of monocyte recruitment in response to various inflammatory stimuli and a reduction of inflammatory lesions in models of demyelinating disease. In the present study, we compared nociceptive responses in inflammatory and neuropathic models of pain in CCR2 knockout and wild-type mice. In acute pain tests, responses were equivalent in CCR2 knockout and wild-type mice. In models of inflammatory pain, CCR2 knockout mice showed a 70% reduction in phase 2 of the intraplantar formalin-evoked pain response but only a modest (20–30%) and nonsignificant reduction of mechanical allodynia after intraplantar Freund's adjuvant (CFA). In a model of neuropathic pain, the development of mechanical allodynia was totally abrogated in CCR2 knockout mice. CFA administration induced marked up-regulation of CCR2 mRNA in the skin and a moderate increase in the sciatic nerve and dorsal root ganglia (DRG). In response to nerve ligation, persistent and marked up-regulation of CCR2 mRNA was evident in the nerve and DRG. Disruption of Schwann cells in response to nerve lesion resulted in infiltration of CCR2-positive monocytes/macrophages not only to the neuroma but also to the DRG. Chronic pain also resulted in the appearance of activated CCR2-positive microglia in the spinal cord. Collectively, these data suggest that the recruitment and activation of macrophages and microglia peripherally and in neural tissue may contribute to both inflammatory and neuropathic pain states. Accordingly, blockade of the CCR2 receptor may provide a novel therapeutic modality for the treatment of chronic pain.

{dagger} To whom correspondence should be addressed. E-mail: catherine_abbadie{at}merck.com.

Edited by Tomas Hökfelt, Karolinska Institute, Stockholm, Sweden,

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

Abbreviations: CCR2, chemotactic cytokine receptor 2; CFA, complete Freund's adjuvant; DRG, dorsal root ganglia; MCP-1, monocyte chemoattractant protein 1; -LI, -like immunoreactivity; TNF, tumor necrosis factor; PB, phosphate buffer.

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