Spinal blockage of CXCL1 and its receptor CXCR2 inhibits paclitaxel-induced peripheral neuropathy in mice

Neuropharmacology. 2019 Jun;151:136-143. doi: 10.1016/j.neuropharm.2019.04.014. Epub 2019 Apr 13.

Abstract

Painful peripheral neuropathy is the most dose-limiting side effect of paclitaxel (PTX), a widely used anti-cancer drug to treat solid tumours. The understanding of the mechanisms involved in this side effect is crucial to the development of new therapeutic approaches. CXCL1 chemokine and its receptor CXCR2 have been pointed as promising targets to treat chronic pain. Herein, we sought to evaluate the possible involvement of CXCL1 and CXCR2 in the pathogenesis of PTX-induced neuropathic pain in mice. PTX treatment led to increased levels of CXCL1 in both dorsal root ganglion and spinal cord samples. Systemic treatment with the anti-CXCL1 antibody (10 μg/kg, i.v.) or the selective CXCR2 antagonist (SB225002, 3 mg/kg, i.p.) had minor effect on PTX-induced mechanical hypersensitivity. On the other hand, the intrathecal (i.t.) treatment with anti-CXCL1 (1 ng/site) or SB225002 (10 μg/site) consistently inhibited the nociceptive responses of PTX-treated mice. Similar results were obtained by inhibiting the PI3Kγ enzyme a downstream pathway of CXCL1/CXCR2 signalling with either the selective AS605240 (5 μg/site, i.t.) or the non-selective wortmannin PI3K inhibitor (0.4 μg/site, i.t.). Overall, the data indicates that the up-regulation of CXCL1 is important for the development and maintenance of PTX-induced neuropathic pain in mice. Therefore, the spinal blockage of CXCL1/CXCR2 signalling might be a new innovative therapeutic approach to treat this clinical side effect of PTX.

Keywords: CXCL1; CXCR2; Neuropathic pain; Paclitaxel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / adverse effects*
  • Chemokine CXCL1 / antagonists & inhibitors*
  • Chemokine CXCL1 / metabolism
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / metabolism
  • Mice
  • Neurons / drug effects
  • Neurons / metabolism
  • Paclitaxel / adverse effects*
  • Peripheral Nervous System Diseases / chemically induced
  • Peripheral Nervous System Diseases / drug therapy*
  • Phenylurea Compounds / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Quinoxalines / pharmacology
  • Receptors, Interleukin-8B / antagonists & inhibitors*
  • Receptors, Interleukin-8B / metabolism
  • Signal Transduction / drug effects
  • Spinal Cord / drug effects*
  • Spinal Cord / metabolism
  • Thiazolidinediones / pharmacology

Substances

  • 5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione
  • Antineoplastic Agents, Phytogenic
  • Chemokine CXCL1
  • Phenylurea Compounds
  • Quinoxalines
  • Receptors, Interleukin-8B
  • SB 225002
  • Thiazolidinediones
  • Paclitaxel