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

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 ␤ 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 (L3͞L6) with compressed lumbar DRG (L4͞L5) 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 L4͞L5 and ipsilateral noncompressed L3͞L6 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 L4͞L5 and noncompressed L3͞L6 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-1͞CCR2 signaling is directly involved with a chronic compression injury and may contribute to associated neuronal hyperexcitability and neuropathic pain.hyperalgesia ͉ nerve injury ͉ neuropathic pain ͉ peripheral sensitization I nf lammation accompanying peripheral nerve injury frequently produces neuropathic pain symptoms, such as hyperalgesia and allodynia. This hyperalgesia may reflect ongoing or ectopic changes in the excitability of neurons in both injured and adjacent uninjured dorsal root ganglion (DRG) (1). Mechanisms that may contribute to the changes in neuronal activity include altered expression of ion channels, kinases, enzymes, neuropeptides, transcription factors, neurotrophins, and͞or the de novo presence of proinflammatory mediators such as cytokines, chemokines, and their respective receptors. However, current knowledge of the modification of molecular properties in both injured and noninjured adjacent ganglia is limited.Recent studies implicate the ␤ chemokine receptor 2 (CCR2) in the development and maintenance of pain (2-4). CCR2 is a G protein-coupled receptor that is related in structure to other CCRs (5, 6) and is largely thought to be a major regulator of induced macrophage migration (7-9). CCR2 is also constitutively expressed by different types of cells in the central nervous system, including neurons (10, 11), activated astrocytes (12, 13), microglia (3), and neural progenitor cells (14,15).Most CCRs, including CCR2, bind multiple chemokines (16, 17). CCR2 binds a family of closely related ␤-chemokines (C-C) called monocyte chemoattractant proteins (MCP), of whic...

CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis

“…This process has been demonstrated on cultured (18) and previously injured adult DRG sensory neurons (27,(29)(30)(31)(32). In addition, chemokines are of central importance in the recruitment of leukocytes.…”

Dorsal root compression produces myelinated axonal degeneration near the biomechanical thresholds for mechanical behavioral hypersensitivity

“…Within the first week after neuronal compression, neurons exhibit decreased firing thresholds and increased action potential durations . During that time frame, the progression of Wallerian degeneration can alter electrophysiology and membrane properties in compressed neurons and increase signaling of leukocytes and chemokines, enhancing neuronal excitability in adjacent, surviving axons (Boucher et al, 2000;Li et al, 2000;Brack and Stein, 2003;Obata et al, 2003;Song et al, 2003;White et al, 2005;Tan et al, 2006). While surviving axons can produce aberrant signals after compression, regenerating A-fibers may also re-map to the superficial laminae of the spinal cord (Ramer et al, 1997;Myers, 1999, 2000;Watanabe et al, 2007).…”

Do glial cells control pain?

“…Monocyte chemoattractant protein-1 (MCP-1, also called CCL2) is a well known chemoattractant for microglia. Nerve injury increases MCP-1 expression in the DRG (Tanaka et al, 2004;White et al, 2005;Zhang & De Koninck, 2006). Mice lacking CCR2 show an impaired neuropathic pain (Abbadie et al, 2003).…”