title: Visualization of chemokine receptor activation in transgenic mice reveals peripheral activation of CCR2 receptors in states of neuropathic pain.
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.
authors: Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, Illinois 60611, USA.
authors: Hosung
authors: H
authors: Jung
authors: Sonia
authors: S
authors: Bhangoo
authors: Ghazal
authors: G
authors: Banisadr
authors: Caroline
authors: C
authors: Freitag
authors: Dongjun
authors: D
authors: Ren
authors: Fletcher A
authors: FA
authors: White
authors: Richard J
authors: RJ
authors: Miller
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003711:Demyelinating Diseases / Q000139:chemically induced; D004195:Disease Models, Animal; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010146:Pain / Q000235:genetics / Q000378:metabolism*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000523:psychology; D010525:Peripheral Nerves / Q000187:drug effects / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D054390:Receptors, CCR2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020426:Sciatic Neuropathy / Q000139:chemically induced; D014162:Transfection; D000097573:Red Fluorescent Protein
chemical_list: D018932:Chemokine CCL2; D049452:Green Fluorescent Proteins; D008070:Lipopolysaccharides; D008164:Luminescent Proteins; D054390:Receptors, CCR2; D000097573:Red Fluorescent Protein