The painful
peripheral neuropathy occurring frequently during
chemotherapy with
paclitaxel or
oxaliplatin is one of their dose-limiting factors. We reported previously that
substance P is involved in the pathogenesis of pulmonary
hypersensitivity reaction to
paclitaxel in rats, and an
antiallergic agent pemirolast reverses this reaction via the blockade of release of
substance P. In the present study, we investigated the involvement of
substance P in
paclitaxel-induced
peripheral neuropathy compared with that by
oxaliplatin. In von Frey and
acetone tests in rats repeated administration of
paclitaxel (6 mg/kg i.p., once a week for 4 weeks) or
oxaliplatin (4 mg/kg i.p., twice a week for 4 weeks) induced both
mechanical allodynia and cold
hyperalgesia.
Paclitaxel-induced
peripheral neuropathy was reversed primarily by the acute administration of
pemirolast (0.1 and 1 mg/kg p.o.). Moreover, coadministration of the receptor antagonists neurokinin 1 [N-acetyl-
l-tryptophan 3,5-bis(trifluoromethyl)benzylester (L-732,138), 100 μg/body i.t.] and neurokinin 2 [5-fluoro-3-[2-[4-methoxy-4-[[(R)-phenylsulphinyl]methyl]-1-piperidinyl]ethyl]-1H-
indole (
GR159897), 100 μg/body i.t.] strongly reversed
paclitaxel-induced neuropathy. On the other hand,
oxaliplatin-induced
peripheral neuropathy was not reversed by
pemirolast. In the in vitro study using cultured adult rat dorsal root ganglion neurons
paclitaxel (1000 ng/ml) significantly increased the release of
substance P, and
pemirolast (100 and 1000 nM) significantly inhibited this increase of
substance P release.
Oxaliplatin, by contrast, did not increase the release of
substance P. These results suggest that
substance P is involved in
paclitaxel-induced neuropathy, and the mechanism of its action is clearly different from that of
oxaliplatin.