Chemokines and pain mechanisms

Abstract

The development of new therapeutic approaches to the treatment of painful neuropathies requires a better understanding of the mechanisms that underlie the development of these chronic pain syndromes. It is now well established that astrocytic and microglial cells modulate the neuronal mechanisms of chronic pain in spinal cord and possibly in the brain. In animal models of neuropathic pain following peripheral nerve injury, several changes occur at the level of the first pain synapse between the central terminals of sensory neurons and second order neurons. These neuronal mechanisms can be modulated by pro-nociceptive mediators released by non neuronal cells such as microglia and astrocytes which become activated in the spinal cord following PNS injury. However, the signals that mediate the spread of nociceptive signaling from neurons to glial cells in the dorsal horn remain to be established. Herein we provide evidence for two emerging signaling pathways between injured sensory neurons and spinal microglia: chemotactic cytokine ligand 2 (CCL2)/CCR2 and cathepsin S/CX3CL1 (fractalkine)/CX3CR1. We discuss the plasticity of these two chemokine systems at the level of the dorsal root ganglia and spinal cord demonstrating that modulation of chemokines using selective antagonists decrease nociceptive behavior in rodent chronic pain models. Since up-regulation of chemokines and their receptors may be a mechanism that directly and/or indirectly contributes to the development and maintenance of chronic pain, these molecular molecules may represent novel targets for therapeutic intervention in sustained pain states.

Fig. 1

Cellular distribution of CCL2 in normal rat dorsal root ganglia (DRG). Double labeling immunofluorescence is used to identify the neurochemistry of CCL2-expressing DRG neurons. Numerous substance P (B, in red) ganglion cells colocalize with CCL2 (A, in green). Merged images show dually labeled cells (C, in yellow). Immunohistochemical localization of CCL2 in normal rat spinal dorsal horn by confocal microscopy. Double labeling of CCL2 (D, in green) with substance P (E, in red); colocalization is shown in yellow (F). A dense network of CCL2-immunopositive processes is observed in laminae II of Rexed. At higher magnification there is no apparent overlap between CCL2 and neuropeptides in the inner portion of laminae IIi (arrowheads). Scale bars equal 100 μm.

Fig. 2

Nociceptive responses in CCR2 deficient mice, in mice overexpressing CCL2 and the anti-nociceptive effects of a CCR2 antagonist. (A–C) Example of CCL2/CCR2 contribution to nociceptive behavior in the formalin test duration of licking and lifting in response to intraplantar formalin injection is significantly reduced in the CCR2 knock-out mice as compared to wild-type mice (A), and is significantly increased in mice overexpressing CCL2 as compared to control mice (B). A CCR2 antagonist significantly decreased phase 2 of the formalin test (C). (D) Summary of data in CCR2 deficient mice, CCL2 overexpressing mice (CCL2+ tg) and effects of CCR2 antagonists in nociceptive pain models.

Fig. 3

Time course of cathepsin S expression in the dorsal horn following peripheral nerve injury. Photomicrographs show increased expression of cathepsin S in the ipsilateral dorsal horn of the spinal cord, peaking at 7 days following partial nerve ligation. Scale bars = 100 μm.