Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2

Abstract

Mice lacking the chemokine receptor chemotactic cytokine receptor 2 (CCR2) have a marked attenuation of monocyte recruitment in response to various inflammatory stimuli and a reduction of inflammatory lesions in models of demyelinating disease. In the present study, we compared nociceptive responses in inflammatory and neuropathic models of pain in CCR2 knockout and wildtype mice. In acute pain tests, responses were equivalent in CCR2 knockout and wild-type mice. In models of inflammatory pain, CCR2 knockout mice showed a 70% reduction in phase 2 of the intraplantar formalin-evoked pain response but only a modest (20 -30%) and nonsignificant reduction of mechanical allodynia after intraplantar Freund's adjuvant (CFA). In a model of neuropathic pain, the development of mechanical allodynia was totally abrogated in CCR2 knockout mice. CFA administration induced marked up-regulation of CCR2 mRNA in the skin and a moderate increase in the sciatic nerve and dorsal root ganglia (DRG). In response to nerve ligation, persistent and marked up-regulation of CCR2 mRNA was evident in the nerve and DRG. Disruption of Schwann cells in response to nerve lesion resulted in infiltration of CCR2-positive monocytes͞macrophages not only to the neuroma but also to the DRG. Chronic pain also resulted in the appearance of activated CCR2-positive microglia in the spinal cord. Collectively, these data suggest that the recruitment and activation of macrophages and microglia peripherally and in neural tissue may contribute to both inflammatory and neuropathic pain states. Accordingly, blockade of the CCR2 receptor may provide a novel therapeutic modality for the treatment of chronic pain.T he chemotactic cytokine or chemokine receptor family is the largest family of G protein-coupled receptors. Accordingly, the number of chemokines that binds to these receptors is large, with Ͼ50 chemokine peptides having been identified to date (for review, see ref. 1). Chemokine biology is further complicated by individual chemokines interacting with more than one receptor and chemokine receptors potentially binding more than one chemokine. Predominantly, chemokine receptors are expressed by leukocytes, and the specific interactions of chemokines with their cognate receptors are major determinants of the trafficking and localization of leukocyte subsets within tissue compartments. A subset of chemokines exhibit potent chemoattractant activity for monocytes; one of them, monocyte chemoattractant protein 1 (MCP-1), stimulates monocyte transendothelial migration (extravasation) and preferentially binds to the chemotactic cytokine receptor (CCR), CCR2. Mice lacking either MCP-1 or CCR2 show a marked attenuation of monocyte recruitment in response to various inflammatory stimuli, as well as a reduction in the development of inflammatory lesions in models of CNS demyelinating disease (2, 3). Moreover, in CCR2-deficient mice, macrophage recruitment to sites of neuronal damage is reduced, with a consequent decrease in demyelination (4, 5).Although inflammatory ...

An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat

“…Previous studies following axotomy of primary afferent sensory nerves has been shown to promote the activation and migration of macrophages within the peripheral nerve (Myers et al, 1996;Tofaris et al, 2002;Abbadie et al, 2003) and associated DRG (Hu & McLachlan, 2002). The increased number of macrophages observed may be due to proliferation of resident macrophages or due to infiltration of hematogeneous macrophages into the DRG (Mueller et al, 2003).…”

Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated μ-Opioid Receptor–Gs Coupling

“…Animal models of neuropathic pain have shown that nerve injury induces a host of pronociceptive, neuroplastic changes, including an upregulation of dynorphin in the spinal cord, enhanced levels of cholecystokinin, increased activation of phosphorylated p38 MAP kinase, and increased content and evoked release of substance P and CGRP. [1][2][3][4]10,34,52,66,80 Upregulation of cytokine receptor mRNA in the sciatic nerve and dorsal root ganglion after partial spinal nerve ligation has been noted, and SNL has also been reported to decrease MOR density in injured peripheral axons in the ipsilateral Lamina I of dorsal horn, leading to changes in presynaptic-and postsynapticevoked responses of MOR-containing fiber. 2,46,59 These synaptic changes include a decrease in presynaptic MOR-mediated inhibition, reduced inhibition of the miniature EPSP in substantia gelatinosa neurons, a shortened afterhy-perpolarization duration in C-fibers in the L 5 dorsal root ganglion, and increased repetitive firing of Aδ-fibers during sustained depolarization.…”

Do glial cells control pain?

“…Nerve injury increases MCP-1 expression in the DRG (Tanaka et al, 2004;White et al, 2005;Zhang & De Koninck, 2006). Mice lacking CCR2 show an impaired neuropathic pain (Abbadie et al, 2003). Intrathecal injection of MCP-1 activates microglia in wild-type but not in CCR2-deficient mice .…”

“…Fortunately, in last several years, we have seen several potential markers, such as the ATP receptor P2X4 (Tsuda et al, 2003), the chemokine receptors CCR2 (Abbadie et al, 2003) and CX3CR1 Zhuang et al, 2007), as well as Toll-like recepotor-4 (TLR4) (Tanga et al, 2005).…”