Visualization of Chemokine Receptor Activation in Transgenic Mice Reveals Peripheral Activation of CCR2 Receptors in States of Neuropathic Pain
- 24 June 2009
- journal article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 29 (25), 8051-8062
- https://doi.org/10.1523/jneurosci.0485-09.2009
Abstract
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.Keywords
This publication has 55 references indexed in Scilit:
- Pathological and protective roles of glia in chronic painNature Reviews Neuroscience, 2009
- Further evidence for a crucial role of resident endoneurial macrophages in peripheral nerve disorders: Lessons from acrylamide-induced neuropathyGlia, 2008
- Monocyte-Mediated Defense Against Microbial PathogensAnnual Review of Immunology, 2008
- The Chemokine CXCL1/Growth Related Oncogene Increases Sodium Currents and Neuronal Excitability in Small Diameter Sensory NeuronsMolecular Pain, 2008
- Chemokines and the pathophysiology of neuropathic painProceedings of the National Academy of Sciences, 2007
- Activation of the nuclear factor of activated T-cells (NFAT) mediates upregulation of CCR2 chemokine receptors in dorsal root ganglion (DRG) neurons: A possible mechanism for activity-dependent transcription in DRG neurons in association with neuropathic painMolecular and Cellular Neuroscience, 2007
- Monocyte chemoattractant protein‐1 functions as a neuromodulator in dorsal root ganglia neuronsJournal of Neurochemistry, 2007
- Delayed Functional Expression of Neuronal Chemokine Receptors Following Focal Nerve Demyelination in the Rat: A Mechanism for the Development of Chronic Sensitization of Peripheral NociceptorsMolecular Pain, 2007
- Chemokine receptor expression by neural progenitor cells in neurogenic regions of mouse brainJournal of Comparative Neurology, 2006
- Modulating CCR2 and CCL2 at the blood–brain barrier: relevance for multiple sclerosis pathogenesisBrain, 2005