Monocyte chemoattractant protein-1 functions as a neuromodulator in dorsal root ganglia neurons.
It has previously been observed that expression of chemokine monocyte chemoattractant protein-1 (MCP-1/CC chemokine ligand 2 (CCL2)) and its receptor CC chemokine receptor 2 (CCR2) is up-regulated by dorsal root ganglion (DRG) neurons in association with rodent models of neuropathic pain. MCP-1 increases the excitability of nociceptive neurons after a peripheral nerve injury, while disruption of MCP-1/CCR2 signaling blocks the development of neuropathic pain, suggesting MCP-1 signaling is responsible for heightened pain sensitivity. To define the mechanisms of MCP-1 signaling in DRG, we studied intracellular processing, release, and receptor-mediated signaling of MCP-1 in DRG neurons. We found that in a focal demyelination model of neuropathic pain both MCP-1 and CCR2 were up-regulated by the same neurons including transient receptor potential vanilloid receptor subtype 1 (TRPV1) expressing nociceptors. MCP-1 expressed by DRG neurons was packaged into large dense-core vesicles whose release could be induced from the soma by depolarization in a Ca2+-dependent manner. Activation of CCR2 by MCP-1 could sensitize nociceptors via transactivation of transient receptor potential channels. Our results suggest that MCP-1 and CCR2, up-regulated by sensory neurons following peripheral nerve injury, might participate in neural signal processing which contributes to sustained excitability of primary afferent neurons.
Jung
Hosung
H
Department of Molecular Pharmacology & Biological Chemistry and Interdepartmental Neuroscience Program, Northwestern University, Chicago, Illinois 60611, USA.
Toth
Peter T
PT
White
Fletcher A
FA
Miller
Richard J
RJ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002461:Cell Line, Transformed; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005727:Ganglia, Spinal / Q000166:cytology*; D005786:Gene Expression Regulation / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011134:Polysaccharides; D054390:Receptors, CCR2 / Q000235:genetics / Q000502:physiology*; D020426:Sciatic Neuropathy / Q000139:chemically induced / Q000378:metabolism; D014162:Transfection / Q000379:methods
C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D011134:Polysaccharides; D054390:Receptors, CCR2; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D002211:Capsaicin; D002118:Calcium