Painful
peripheral neuropathy is a dose-limiting side effect of
paclitaxel therapy, which hampers the optimal clinical management of
chemotherapy in
cancer patients. Currently the underlying mechanisms remain largely unknown. Here we showed that the clinically relevant dose of
paclitaxel (3×8mg/kg, cumulative dose 24mg/kg) induced significant upregulation of the
chemokine CX3CL1 in the A-fiber primary sensory neurons in vivo and in vitro and infiltration of macrophages into the dorsal root ganglion (DRG) in rats.
Paclitaxel treatment also increased cleaved
caspase-3 expression, induced the loss of primary afferent terminal fibers and decreased sciatic-evoked A-fiber responses in the spinal dorsal horn, indicating DRG neuronal apoptosis induced by
paclitaxel. In addition, the
paclitaxel-induced DRG neuronal apoptosis occurred exclusively in the presence of macrophage in vitro study. Intrathecal or systemic injection of CX3CL1
neutralizing antibody blocked
paclitaxel-induced macrophage recruitment and neuronal apoptosis in the DRG, and also attenuated
paclitaxel-induced
allodynia. Furthermore, depletion of macrophage by systemic administration of
clodronate inhibited
paclitaxel-induced
allodynia. Blocking CX3CL1 decreased activation of
p38 MAPK in the macrophage, and inhibition of
p38 MAPK activity blocked the neuronal apoptosis and development of
mechanical allodynia induced by
paclitaxel. These findings provide novel evidence that CX3CL1-recruited macrophage contributed to
paclitaxel-induced DRG neuronal apoptosis and painful
peripheral neuropathy.