Analgesic effects evoked by a CCR2 antagonist or an anti‐CCL2 antibody in inflamed mice

Abstract

Chemokine CCL2, also known as monocyte chemoattractant protein-1 (MCP-1), is a molecule that in addition to its well-established role in chemotaxis can also act as nociceptor sensitizer. The upregulation of this chemokine in inflamed tissues could suggest its involvement in inflammatory hypernociception. Thus, we have measured CCL2 levels in mice with acute or chronic inflammation due to the intraplantar (i.pl.) injection of carrageenan or complete Freund's adjuvant (CFA), respectively, and we have studied whether inflammatory hyperalgesia or allodynia could be attenuated by blocking CCR2 receptors or neutralizing CCL2 with an anti-CCL2 antibody. A remarkable increase in CCL2 concentration was detected by ELISA in paw homogenates coming from carrageenan- or CFA-inflamed mice, being its expression mainly localized in macrophages, as shown by immunohistochemical assays. The s.c. (0.3-3 mg/kg) or i.pl. (0.3-3 μg) administration of the CCR2 antagonist, RS 504393, dose dependently inhibited thermal hyperalgesia measured in acutely or chronically inflamed mice, whereas s.c. administration of this drug did not reduce inflammatory mechanical allodynia. Furthermore, the inhibition of inflammatory hyperalgesia after the administration of an anti-CCL2 antibody (0.1-1 μg; i.pl.) suggests that CCL2 could be the endogenous chemokine responsible for CCR2-mediated hyperalgesic effects. Besides, the acute administration of the highest antihyperalgesic dose of RS 504393 assayed did not reduce paw tumefaction or modify the presence of inflammatory cells. These results indicate that the blockade of the CCL2/CCR2 system can counteract inflammatory hyperalgesia, being this antinociceptive effect unrelated to a decrease in the inflammatory reaction.

Mechanistic Insights Into the Role of the Chemokine CCL2/CCR2 Axis in Dorsal Root Ganglia to Peripheral Inflammation and Pain Hypersensitivity

“…Interestingly, despite the increase in CCL2 mRNA expression and release by CFA-exposed nociceptors, immunohistochemical analysis of ligated nerves reveals no increased CCL2 immunoreactivity in CFA-treated animals, ruling out the contribution of a DRG-derived CCL2 release toward the periphery, at least at day 10 post-CFA. This is consistent with the demonstration that CCL2 is locally produced at the in ammation site by macrophages/monocytes in CFA in amed rats and that treatment with INCB3344 dose-dependently inhibits macrophage in ux [47,79]. As previously shown [19], CCL2 is probably conveyed to the terminals of nociceptors and released at the spinal dorsal horn to modulate the activity of post-synaptic neurons and surrounding glial cells.…”

“…injection of INCB3344 exerted tactile allodynia as previously observed in neuropathic, postoperative and cancer-induced bone pain models using anti-CCL2 antibodies and small molecule antagonists of CCR2 [15,21,[97][98][99][100][101][102][103]. In contrast, inhibition of CCR2 using intraplantar or subcutaneous injection of the antagonist RS504393 was only effective in revering thermal hyperalgesia in CFA in amed mice [79]. Importantly, this decrease in mechanical hypersensitivity was accompanied by a reduction in the ambulation-evoked pain behaviors in freely-moving CFA-treated rats.…”

Chemokine (c-c motif) receptor 2 mediates mechanical and cold hypersensitivity in sickle cell disease mice

“…This dose has previously been effective in reducing paclitaxel-induced hyperalgesia [46]. In additional experiments, intrathecal RS 504393 (3 μg/5 μL; dose effective in reducing bone cancer thermal hyperalgesia [45]) administration was performed 30 min prior to behavioral testing, or intraplantar RS 504393 (3 μg/10 μL; dose effective in reducing carrageenan-induced thermal hyperalgesia [33]) was administered 60 min prior to behavioral testing. The CCR4 antagonist C 021 dihydrochloride (3 mg/kg; Tocris) or PBS vehicle was injected subcutaneously into the neck 30 minutes prior to testing.…”

Functional inhibition of chemokine receptor CCR2 by dicer-substrate-siRNA prevents pain development

“…10–12 Accordingly, CCR2 receptor antagonists successfully inhibit nociceptive signaling in acute, inflammatory, and neuropathic pain in animal models. 11,13–18 These behavioral observations are further supported by genetic evidence as CCL2 overexpressing mice show greater nociceptive responses in both thermal and chemical stimulus modalities. 19 In addition, CCR2-deficient mice exhibit decreased nociceptive behaviors to formalin-induced prolonged noxious stimulation, fail to develop neuropathic pain, and do not display movement-evoked pain behaviors in osteoarthritis.…”