Delayed Functional Expression of Neuronal Chemokine Receptors Following Focal Nerve Demyelination in the Rat: A Mechanism for the Development of Chronic Sensitization of Peripheral Nociceptors

Abstract

BackgroundAnimal and clinical studies have revealed that focal peripheral nerve axon demyelination is accompanied by nociceptive pain behavior. C-C and C-X-C chemokines and their receptors have been strongly implicated in demyelinating polyneuropathies and persistent pain syndromes. Herein, we studied the degree to which chronic nociceptive pain behavior is correlated with the neuronal expression of chemokines and their receptors following unilateral lysophosphatidylcholine (LPC)-induced focal demyelination of the sciatic nerve in rats.ResultsFocal nerve demyelination increased behavioral reflex responsiveness to mechanical stimuli between postoperative day (POD) 3 and POD28 in both the hindpaw ipsilateral and contralateral to the nerve injury. This behavior was accompanied by a bilateral increase in the numbers of primary sensory neurons expressing the chemokine receptors CCR2, CCR5, and CXCR4 by POD14, with no change in the pattern of CXCR3 expression. Significant increases in the numbers of neurons expressing the chemokines monocyte chemoattractant protein-1 (MCP-1/CCL2), Regulated on Activation, Normal T Expressed and Secreted (RANTES/CCL5) and interferon γ-inducing protein-10 (IP-10/CXCL10) were also evident following nerve injury, although neuronal expression pattern of stromal cell derived factor-1α (SDF1/CXCL12) did not change. Functional studies demonstrated that acutely dissociated sensory neurons derived from LPC-injured animals responded with increased [Ca2+]i following exposure to MCP-1, IP-10, SDF1 and RANTES on POD 14 and 28, but these responses were largely absent by POD35. On days 14 and 28, rats received either saline or a CCR2 receptor antagonist isomer (CCR2 RA-[R]) or its inactive enantiomer (CCR2 RA-[S]) by intraperitoneal (i.p.) injection. CCR2 RA-[R] treatment of nerve-injured rats produced stereospecific bilateral reversal of tactile hyperalgesia.ConclusionThese results suggest that the presence of chemokine signaling by both injured and adjacent, uninjured sensory neurons is correlated with the maintenance phase of a persistent pain state, suggesting that chemokine receptor antagonists may be an important therapeutic intervention for chronic pain.

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.…”

“…These models included chronic constriction injury (26), unilateral gp120 sciatic nerve administration (27), partial ligation of the sciatic nerve (28), and focal nerve demyelination (29). Mechanical allodynia after nerve injury has been reported to be inhibited by treatment with a CCR2 receptor antagonist (27,29), and Ccr2-null mice were protected from mechanical allodynia after nerve injury but not during acute inflammatory pain tests (21). We find here that Ccr2-null mice initially develop mechanical allodynia (first phase), but it resolves in the absence of MCP-1/CCR2 signaling.…”

“…At 4 and 8 wk postsurgery, cells were acutely isolated from innervating DRG of three to four mice via collagenase 4 (1 mg/mL) and papain (30 U/mL; Worthington Biochemical) digestion. Cells were plated on poly-L-lysine and laminin-(20 μg/mL) coated glass coverslips (18), and cultured at 37°C with 5% CO 2 for 4 d in adult neurogenic medium: F12 with L-glutamine, 0.5% FBS, 1× N2 (Life Technologies), penicillin and streptomycin (100 μg/mL and 100 U/mL) (29).…”

The Chemokine CCL2 Increases Nav1.8 Sodium Channel Activity in Primary Sensory Neurons through a Gβγ-Dependent Mechanism

“…Accordingly, CCL2-overexpressing or CCR2-deficient mice exhibited altered nociceptive behaviors to thermal, chemical, and mechanical stimuli (Abbadie et al, 2003;Menetski et al, 2007;Zhang et al, 2007). In addition, the use of CCR2 receptor antagonists or blocking antibodies successfully inhibited nociceptive signaling (Bhangoo et al, 2007Serrano et al, 2010;Struthers and Pasternak, 2010;Van Steenwinckel et al, 2011). Similar to pain neuromodulators (Rostène et al, 2007), CCL2 is stored in large dense core vesicles known to contain pronociceptive-related peptides [substance P and CGRP (calcitonin gene-related peptide)], is released in a calcium-dependent manner from DRG neuronal cell bodies and terminal nerve endings, and directly excites primary nociceptive neurons by autocrine/paracrine processes (Oh et al, 2001;White et al, 2005;Sun et al, 2006;Dansereau et al, 2008;Jung et al, 2008;Van Steenwinckel et al, 2011).…”

Chemokine ligand 2 in the trigeminal ganglion regulates pain induced by experimental tooth movement

“…Similar up-regulation was found in previous studies using other rodent models for neuropathic pain in the DRG or TG. These models included unilateral application of glycoprotein 120 into the sciatic nerve, 27 chronic constriction injury, 28 partial ligation of the sciatic nerve, 29 focal nerve demyelination, 30 and experimental osteoarthritis. 16 However, the change rhythms in CCL2 expression were different in some cases.…”