Excitatory monocyte chemoattractant protein-1 signaling is up-regulated in sensory neurons after chronic compression of the dorsal root ganglion

doi:10.1073/pnas.0503496102

Excitatory monocyte chemoattractant protein-1 signaling is up-regulated in sensory neurons after chronic compression of the dorsal root ganglion

Departments of ^*Cell Biology, Neurobiology, and Anatomy, and ^†Anesthesiology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153; ^¶Neurogen Corporation, Branford, CT 06405; ^§Department of Anesthesiology, Yale University School of Medicine, New Haven, CT 06510; and ^∥Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD (received for review April 27, 2005)

Abstract

Neuronal hyperexcitability in both injured and adjacent uninjured neurons is associated with states of chronic injury and pain and is likely subject to neuroinflammatory processes. Chronic inflammatory responses are largely orchestrated by chemokines. One chemokine, monocyte chemoattractant protein-1 (MCP-1), in the presence of its cognate receptor, the β chemokine receptor 2 (CCR2), produces neural activity in dissociated neuronal cultures of neonatal dorsal root ganglion (DRG) neurons. Using a neuropathic pain model, chronic compression of the DRG (CCD), we compared anatomically separate populations of noncompressed lumbar DRG (L3/L6) with compressed lumbar DRG (L4/L5) for changes in the gene expression of CCR2. In situ hybridization revealed that CCR2 mRNA was up-regulated in neurons and nonneuronal cells present in both compressed L4/L5 and ipsilateral noncompressed L3/L6 DRGs at postoperative day 5 (POD5). The total percentages of compressed and noncompressed neurons exhibiting CCR2 mRNA transcripts in L3, L5, and L6 DRG were 33 ± 3.5%, 49 ± 6.2%, and 41 ± 5.6%, respectively, and included cell bodies of small, medium, and large size. In addition, the preferred CCR2 ligand, MCP-1, was up-regulated by POD5 in both compressed L4/L5 and noncompressed L3/L6 DRG neurons. Application of MCP-1 to the cell bodies of the intact formerly compressed DRG in vitro produced potent excitatory effects not observed in control ganglia. MCP-1/CCR2 signaling is directly involved with a chronic compression injury and may contribute to associated neuronal hyperexcitability and neuropathic pain.

Footnotes

↵ ‡ To whom correspondence should be addressed. E-mail: fwhite{at}lumc.edu.
Author contributions: F.A.W., D.N.C., R.H.L., and R.J.M. designed research; F.A.W., J. Sun, C.M., D.R., M.R., and J. Steflik performed research; F.A.W., J. Sun, R.H.L., and R.J.M. analyzed data; S.M.W. contributed new reagents/analytic tools; and F.A.W., S.M.W., R.H.L., and R.J.M. wrote the paper.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: DRG, dorsal root ganglion; CCR2, β chemokine receptor 2; MCP, monocyte chemoattractant protein; Ln, lumbar DRG n; CCD, chronic compression of the DRG; PODn, postoperative day n.
↵ ** Sun, J., Yang, B., Ma, C., Donnelly, D. F. & LaMotte, R. H. (2005) Soc. Neurosci. Abstr., 511.15 (abstr.).