Chemokine signaling and the management of neuropathic pain

Abstract

Chemokines and chemokine receptors are widely expressed in the nervous system, where they play roles in the regulation of stem cell migration, axonal path finding, and neurotransmission. Chemokine signaling is also of key importance in the regulation of neuroinflammatory responses. The expression of the chemokine monocyte chemoattractant protein 1 (MCP1) and its receptor (CCR2) is upregulated by dorsal root ganglia neurons in rodent models of neuropathic pain. MCP1 increases the excitability of nociceptive neurons after a peripheral nerve injury, and disruption of MCP1 signaling blocks the development of neuropathic pain. In the spinal cord, microglial cells expressing CCR2 are thought to play an active role in the initiation and maintenance of pain hypersensitivity, and MCP1 may also alter the excitability of spinal neurons in some cases. Other predominant sites of CCR2 activation are found in the peripheral nervous system, thereby explaining, at least in some circumstances, the rapid anti-nociceptive effects of peripherally administered CCR2 antagonists. In this article we discuss the relative roles of CCR2 activation in the peripheral and central nervous systems in relation to the phenomenon of neuropathic pain.

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Fletcher A. White, PhD, is an associate professor at the Stritch School of Medicine at Loyola University, Chicago, with a joint appointment in Cell Biology, Neurobiology and Anatomy, and Anesthesiology. His research group studies the sequence and nature of the neuroinflammatory events that govern neuron and non-neuronal communication in the sensory ganglia. Many of these events may be critical for the discovery of new mechanisms and targets for chronic pain treatment. Address correspondence to FAW. E-mail fwhite@lumc.edu

Richard J. Miller, PhD, is the Alfred Newton Richards Professor of Pharmacology at Northwestern Medical School in Chicago. He obtained his PhD at Cambridge University, UK, and subsequently worked for Burroughs-Wellcome & Company. He then joined the Pharmacology Department at the University of Chicago, , where he worked for twenty-five years before moving to Northwestern University in 2000. His laboratory works on receptors, signal transduction, and synaptic communication in the nervous system, as well as mechanisms of neurodegenerative disease.

Polina Feldman, BS, graduated from University of Wisconsin-Madison in 2007, where she studied biology and psychology. She is currently pursuing her doctoral degree under the direction of Fletcher A. White in the Neuroscience Graduate Program at Loyola University, Chicago. Her research focuses on the neuroinflammatory response in the peripheral nervous system following injury. Specifically, she is investigating the degree to which chemokines contribute to chronic pain syndromes.

Figure 1

CCR2 signaling is activated in the DRG. Mice expressing MCP1 tagged with monomeric red fluorescent protein-1 (MCP1–mRFP1) were crossed with mice expressing CCR2 tagged with extra green fluorescent protein (CCR2–EGFP) mice. The resultant transgenic mice were subjected to lysophosphatidylcholine-(LPC)-induced demyelination of the sciatic nerve. In the DRG ipsilateral to the injury, expression of both MCP1 and CCR2 increased (D–F), whereas there was little expression of MCP1 or CCR2 under naive conditions (A–C). MCP1–mRFP1 mainly localized to neurons (large red arrow) and, to some extent, to satellite glia [small red arrow (D)]. CCR2–EGFP localized to neurons (large green arrow) and satellite glia [small green arrow (E)]. Most CCR2–EGFP-expressing neurons and satellite glia also contained MCP1–mRFP1 [yellow arrow (F)]. Injection of the CCR2–RA eliminated MCP1–mRFP1 in satellite glia [small green arrow (G–I)]. Also, after CCR2–RA treatment, MCP1–mRFP1- and CCR2–EGFP-expressing cells existed as separate populations [large green and red arrows(G–I)]. Cross-sectional images across the white lines are shown right to (F) and (I). (J, K) Intensities of mRFP1 and EGFP in shorter white lines in (F) and (I) are expressed in arbitrary units to compare relative signal intensities among different cells. (J) In the LPC group, most neurons that express CCR2–EGFP also contain MCP1–mRFP1. Also, the CCR2–EGFP signal in neurons is relatively weaker than the signal in satellite glia (J). (K) In the LPC plus CCR2–RA group, however, most CCR2–EGFP-expressing cells do not contain significant amount of MCP1–mRFP1 signal. In addition, the CCR2–EGFP signal in neurons is now as strong as the signal in satellite glia (K).

Figure 2

Peripheral nerve demyelination induces CCR2. CCR2–mRNA is induced in both the site of the nerve injury and in the sensory neurons of the dorsal root ganglion (DRG), but not in the associated spinal cord. (A) Neither the MCP1 monomeric red fluorescent protein-1 (MCP1–mRFP1) nor the CCR2 extra green fluorescent protein CCR2–EGFP in transgenic mice subjected to LPC-induced demyelination of the sciatic nerve exhibited expression of MCP1 or CCR2 at a detectable level. Leukocytes outside the spinal cord were clearly visible (green arrow). (B–D) CCR2 expression was also examined at the mRNA level by in situ hybridization. The spinal cord does not contain significant CCR2-expressing cellular components (B), whereas many cells in the sciatic nerve (C) and DRG (D) express CCR2 receptors in the LPC group. DH, Dorsal horn; DC, dorsal column.

Figure 3

MCP1 as a chemokine in pain conditions. MCP1 may act at multiple sites and the precise nature of its involvement may differ in different pain conditions. (A) Schwann cells and/or endoneurial fibroblasts in injured axons upregulate MCP1, which then attracts macrophages into the nerve. Infiltrating macrophages may then secrete inflammatory molecules that sensitize the nerve. (B) Neurons in the DRG also upregulate both MCP1 and CCR2. The activation of CCR2 signaling in DRG neurons is excitatory and therefore pronociceptive. (C) DRG neurons may transport MCP1 to central nerve endings in the spinal cord where it is released. Once released in the spinal cord, MCP1 may activate secondary neurons and some CCR2+ leukocytes. Some neurons have been reported to express CCR2, and activation of CCR2 in these neurons may inhibit their response to GABAergic input (C).