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 (10mg/kg) was inhibited by the s.c. (0.3-3mg/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.