Spinal CCL2 and microglial activation are involved in paclitaxel-evoked cold hyperalgesia |
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| Institution: | 1. Center for Brain and Spinal Cord Repair, USA;2. Department of Neuroscience, Wexner Medical Center, The Ohio State University, Columbus, OH, USA;3. Division of Biostatistics, The Ohio State University, College of Public Health, Columbus, OH, USA;4. Department of Physiology and Cell Biology, Wexner Medical Center, The Ohio State University, Columbus, OH, USA;1. Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States of America;2. Center for Veterinary Medicine, U.S. Food and Drug Administration, Rockville, MD, United States of America;3. Department of Psychiatry, Yale University School of Medicine, Yale Tobacco Center of Regulatory Science, New Haven, CT, United States of America;4. Department of Neurology, Virginia Commonwealth University, Richmond, VA, United States of America;5. Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, United States of America;6. Translational Research Initiative for Pain and Neuropathy, Virginia Commonwealth University, Richmond, VA, United States of America;7. Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, United States of America;8. Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL, United States of America;9. Department of Anatomy and Neurobiology, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States of America |
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| Abstract: | The antineoplastic paclitaxel induces a sensory neuropathy that involves the spinal release of neuroinflammatory mediators and activation of glial cells. Although the chemokine CCL2 can evoke glial activation and its participation in neuropathic pain has been demonstrated in other models, its involvement in paclitaxel-evoked neuropathy has not been previously explored. Paclitaxel-evoked cold hypernociception was assessed in mice by the unilateral cold plate test and the effects on cold hyperalgesia of the CCR2 antagonist RS 504393, the CCR1 antagonist J113863, the microglial inhibitor minocycline or an anti-CCL2 antibody were tested. Furthermore, ELISA measurements of CCL2 concentration and immunohistochemical assays of Iba-1 and GFAP, markers of microglial and astroglial cells respectively, were performed in the lumbar spinal cord.Cold hypernociception measured 3 days after the administration of paclitaxel (10 mg/kg) was inhibited by the s.c. (0.3–3 mg/kg) or i.t. (1–10 μg) administration of RS 504393 but not of J113863 (3–30 mg/kg). CCL2 levels measured by ELISA in the lumbar spinal cord were augmented in mice treated with paclitaxel and the i.t. administration of an anti-CCL2 antibody completely suppressed paclitaxel-evoked cold hyperalgesia, strongly suggesting that CCL2 is involved in the hypernociception evoked by this taxane. Besides, the implication of microglial activation is supported by the increase in the immunolabelling of Iba-1, but not GFAP, in the spinal cord of paclitaxel-treated mice and by the inhibition of cold hyperalgesia produced by the i.t. administration of the microglial inhibitor minocycline (1–10 nmol). Finally, the neutralization of spinal CCL2 by the i.t. administration of a selective antibody for 3 days almost totally inhibited paclitaxel-evoked microglial activation.In conclusion, our results indicate that paclitaxel-evoked cold hypernociception depends on the activation of CCR2 due to the spinal release of CCL2 and the subsequent microglial activation. |
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| Keywords: | Paclitaxel Cold hyperalgesia CCL2 Minocycline Microglia Spinal cord |
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