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The Journal of Neuroscience, June 24, 2009, 29(25):8051-8062; doi:10.1523/JNEUROSCI.0485-09.2009

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Cellular/Molecular
Visualization of Chemokine Receptor Activation in Transgenic Mice Reveals Peripheral Activation of CCR2 Receptors in States of Neuropathic Pain

Hosung Jung,¹ Sonia Bhangoo,¹ Ghazal Banisadr,¹ Caroline Freitag,¹ Dongjun Ren,¹ Fletcher A. White,^2,3 and Richard J. Miller¹

¹Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, Illinois 60611, and ²Departments of Cell Biology, Neurobiology, and Anatomy, and ³Anesthesiology, Loyola University Chicago, Maywood, Illinois 60153

Correspondence should be addressed to Richard J. Miller, Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611. Email: r-miller10{at}northwestern.edu

CCR2 chemokine receptor signaling has been implicated in the generation of diverse types of neuropathology, including neuropathic pain. For example, ccr2 knock-out mice are resistant to the establishment of neuropathic pain, and mice overexpressing its ligand, monocyte chemoattractant protein-1 (MCP1; also known as CCL2), show enhanced pain sensitivity. However, whether CCR2 receptor activation occurs in the central or peripheral nervous system in states of neuropathic pain has not been clear. We developed a novel method for visualizing CCR2 receptor activation in vivo by generating bitransgenic reporter mice in which the chemokine receptor CCR2 and its ligand MCP1 were labeled by the fluorescent proteins enhanced green fluorescent protein and monomeric red fluorescent protein-1, respectively. CCR2 receptor activation under conditions such as acute inflammation and experimental autoimmune encephalomyelitis could be faithfully visualized by using these mice. We examined the status of CCR2 receptor activation in a demyelination injury model of neuropathic pain and found that MCP1-induced CCR2 receptor activation mainly occurred in the peripheral nervous system, including the injured peripheral nerve and dorsal root ganglia. These data explain the rapid antinociceptive effects of peripherally administered CCR2 antagonists under these circumstances, suggesting that CCR2 antagonists may ameliorate pain by inhibiting CCR2 receptor activation in the periphery. The method developed here for visualizing CCR2 receptor activation in vivo may be extended to G-protein-coupled receptors (GPCRs) in general and will be valuable for studying intercellular GPCR-mediated communication in vivo.

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Received Jan. 28, 2009; revised May 7, 2009; accepted May 15, 2009.

Correspondence should be addressed to Richard J. Miller, Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611. Email: r-miller10{at}northwestern.edu

This article has been cited by other articles:

				F. A. White, P. Feldman, and R. J. Miller Chemokine Signaling and the Management of Neuropathic Pain Mol. Interv., August 1, 2009; 9(4): 188 - 195. [Abstract] [Full Text] [PDF]

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