PAIN Summary
Highlight from PAIN (Volume 159, Issue 7, July 2018)
Chemokine CCL2 and Its Receptor CCR2 in the Dorsal Root Ganglion Contribute to Oxaliplatin-Induced Mechanical Hypersensitivity
Amina M. Illias, Andrea C. Gist, Haijun Zhang, Alyssa K. Kosturakis, Patrick M. Dougherty
- Department of Anesthesiology and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
- Department of Anesthesiology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan
Oxaliplatin is a second-generation platinum-based chemotherapy drug that commonly is used to treat colorectal cancer. Like many other anticancer agents, chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of oxaliplatin treatment and is the main dose-limiting toxicity associated with this drug.
One mechanism contributing to the generation of CIPN produced by another agent, paclitaxel, is the activation of innate immune mechanisms in the dorsal root ganglion (DRG) and spinal dorsal horn. Paclitaxel increases the signaling of Toll-like receptor 4 in DRG neurons, which leads to increased expression of C-C chemokine ligand 2 (CCL2), also called monocyte chemotactic protein 1. CCL2 and its receptor, C-C chemokine receptor 2 (CCR2), are key players in the attraction of monocytes to sites of injury and inflammation.
The goal of this work was to test generalizability of a role for CCL2/CCR2 signaling within the DRG in the development of oxaliplatin-related CIPN. The development of oxaliplatin-induced mechanical hypersensitivity was assessed by behavior testing, and changes in CCL2/CCR2 expression in DRG neurons were tested using immunohistochemistry. The expectation was that increased expression of CCL2/CCR2 would accompany mechanical hypersensitivity. Mechanistic linkage between these observations was tested using intrathecal anti-CCL2 antibodies concurrently during and after oxaliplatin treatment.
The main findings were that CCL2 and its receptor CCR2 are increased in the DRG after oxaliplatin treatment in parallel to the development of mechanical hypersensitivity. In addition, intrathecal treatment with an anti-CCL2 antibody during oxaliplatin administration prevents the development of mechanical hypersensitivity, and intrathecal anti-CCL2 antibody treatment also transiently reverses pre-established oxaliplatin-induced mechanical hypersensitivity. These data seem to confirm that there is a generalizability of mechanisms across CIPN models produced using chemotherapy drugs with very different anticancer actions, and effects of the innate immune response in these mechanisms appear to be implicated.
Induction of CCL2/CCR2 signaling in DRG after administration of single-dose oxaliplatin contributes to increased mechanical allodynia, and blocking this signal could be useful both as prophylaxis against neuropathy and as a salvage measure for patients previously treated with oxaliplatin.
