Monocyte chemoattractant protein-1 functions as a neuromodulator in dorsal root ganglia neurons

J Neurochem. 2008 Jan;104(1):254-63. doi: 10.1111/j.1471-4159.2007.04969.x. Epub 2007 Oct 18.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Capsaicin / pharmacology
  • Cell Line, Transformed
  • Chemokine CCL2 / metabolism
  • Disease Models, Animal
  • Drug Interactions
  • Enzyme-Linked Immunosorbent Assay / methods
  • Ganglia, Spinal / cytology*
  • Gene Expression Regulation / physiology*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Mice
  • Mice, Transgenic
  • Neurons / drug effects
  • Neurons / metabolism*
  • Polysaccharides
  • Receptors, CCR2 / genetics
  • Receptors, CCR2 / physiology*
  • Sciatic Neuropathy / chemically induced
  • Sciatic Neuropathy / metabolism
  • Transfection / methods

Substances

  • Ccl2 protein, mouse
  • Ccr2 protein, mouse
  • Chemokine CCL2
  • Polysaccharides
  • Receptors, CCR2
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Capsaicin
  • Calcium