CCL2 Released from Neuronal Synaptic Vesicles in the Spinal Cord Is a Major Mediator of Local Inflammation and Pain after Peripheral Nerve Injury

Abstract

CCL2 chemokine and its receptor CCR2 may contribute to neuropathic pain development. We tested the hypothesis that injury to peripheral nerves triggers CCL2 release from afferents in the dorsal horn spinal cord (DHSC), leading to pronociceptive effects, involving the production of proinflammatory factors, in particular. Consistent with the release of CCL2 from primary afferents, electron microscopy showed the CCL2 immunoreactivity in glomerular boutons and secretory vesicles in the DHSC of naive rats. Through the ex vivo superfusion of DHSC slices, we demonstrated that the rate of CCL2 secretion was much lower in neonatal capsaicin-treated rats than in controls. Thus, much of the CCL2 released in the DHSC originates from nociceptive fibers bearing TRPV1 ( . These pathological pain-associated changes in the DHSC were mimicked by the intrathecal injection of exogenous CCL2 in naive rats and were prevented by the administration of INCB3344 or ERK inhibitor (PD98059). Finally, mechanical allodynia, which was fully developed 2 weeks after SN-CCI in rats, was attenuated by the intrathecal injection of INCB3344. Our data demonstrate that CCL2 has the typical characteristics of a neuronal mediator involved in nociceptive signal processing and that antagonists of its receptor are promising agents from treating neuropathic pain.

CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis

“…In addition, although our findings are consistent with a role for MCP-1/CCR2 signaling within the DRG, it is also possible that CCR2 signaling is important in the spinal cord. MCP-1/CCR2 may be acting in the dorsal horn, as has been suggested (26,35,36), further contributing to the observed phenotype in the Ccr2-null mice.…”

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

“…In particular, the recent progress in identifying CCR2 antagonists has revealed their effectiveness in reversing the nociceptive behaviors induced by focal nerve demyelination injury or HIV sensory neuropathy (Bhangoo et al, 2007Jung et al, 2009). Accordingly, we recently demonstrated that the selective CCR2 antagonist INCB3344 prevented the pronociceptive action of exogenous intraspinal CCL2 and attenuated tactile allodynia in nerve-injured rats Van Steenwinckel et al, 2011). Here, we therefore evaluated whether treatment of small-and mediumsized sensory neurons with INCB3344 abolished CCL2-induced Na v 1.8 current activation.…”

“…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).…”

An Approach to Identify Nerve Injury-Evoked Changes that Contribute to the Development or Protect Against the Development of Sustained Neuropathic Pain

“…I L -6 ) (Murphy et al, 1999;Osamura et al, 2005;Wang et al, 2007;Wang et al, 2009) or in muscle regeneration (e.g. CCL2) (Lu et al, 2011;Van Steenwinckel et al, 2011;Wang et al, 2010). The contribution of immune mediators to neuropathic pain appears to involve alterations of excitability of primary and secondary sensory neurons; therefore, a more targeted approach such as decreasing their level (and/or production by) at the dorsal root ganglia, and in this way blocking their effects on excitability of primary sensory dorsal root ganglia neurons, could improve their use for treating neuropathic pain.…”