Spinal CCL2 pronociceptive action is no longer effective in CCR2 receptor antagonist‐treated rats

Abstract

A better understanding of the mechanisms linked to chemokine pronociceptive effects is essential for the development of new strategies to better prevent and treat chronic pain. Among chemokines, MCP‐1/CCL2 involvement in neuropathic pain processing is now established. However, the mechanisms by which MCP‐1/CCL2 exerts its pronociceptive effects are still poorly understood. In the present study, we demonstrate that MCP‐1/CCL2 can alter pain neurotransmission in healthy rats. Using immunohistochemical studies, we first show that CCL2 is constitutively expressed by primary afferent neurons and their processes in the dorsal horn of the spinal cord. We also observe that CCL2 is co‐localized with pain‐related peptides (SP and CGRP) and capsaicin receptor (VR1). Accordingly, using in vitro superfusion system of lumbar dorsal root ganglion and spinal cord explants of healthy rats, we show that potassium or capsaicin evoke calcium‐dependent release of CCL2. In vivo, we demonstrate that intrathecal administration of CCL2 to healthy rats produces both thermal hyperalgesia and sustained mechanical allodynia (up to four consecutive days). These pronociceptive effects of CCL2 are completely prevented by the selective CCR2 antagonist (INCB3344), indicating that CCL2‐induced pain facilitation is elicited via direct spinal activation of CCR2 receptor. Therefore, preventing the activation of CCR2 might provide a fruitful strategy for treating pain.

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

“…Thus, the SN-CCI model is markedly attenuated in CCR2 knock-out mice (Abbadie et al, 2003). Moreover, intrathecal injection of CCL2 in rats induces prolonged hyperalgesia and allodynia (Tanaka et al, 2004;Dansereau et al, 2008), these effects being reversed by a CCR2 antagonist . In vitro, CCL2 strongly inhibits GABAergic transmission in primary spinal neurons (Gosselin et al, 2005) and sensitizes nociceptors by activating capsaicin transient receptor potential vanilloid 1 (TRPV1) (Jung et al, 2008).…”

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

“…Among them, the chemokine CCL2 was shown to play a key role in spinal nociceptive processing, notably by sensitizing primary afferent neurons White et al, 2009;White and Miller, 2010;Rostène et al, 2011). Acting via the binding to its cognate GPCR CCR2, intrathecal delivery of exogenous CCL2 was found to promote pain hypersensitivity (Tanaka et al, 2004;Dansereau et al, 2008). 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).…”

CCR2 Receptor Ligands Inhibit Cav3.2 T-Type Calcium Channels

“…Both CCR2 receptors and T-type channels have a pronociceptive function. Knockout of CCR 2 receptors results in a phenotype that is hyposensitive to pain (Abbadie et al, 2003), and intrathecal delivery of CCR2 receptor antagonists is beneficial in the treatment of neuropathic pain (Dansereau et al, 2008;Abbadie et al, 2009). Either short-term block or antisense depletion of Ca v 3.2 T-type calcium channels also mediates analgesia (Matthews and Dickinson, 2001;Bourinet et al, 2005).…”

“…Consistent with a proalgesic action of MCP-1, knockout of CCR2 receptors reduces inflammatory pain and prevents the occurrence of neuropathic pain as a result of chronic construction injury (Abbadie et al, 2003). Likewise, intrathecal administration of CCR2 receptor antagonists alleviates neuropathic pain (Dansereau et al, 2008;Abbadie et al, 2009). Given these proalgesic actions of MCP-1, we wondered whether they might in part arise from an enhancement of activation of N-or T-type calcium channel activity.…”