Prophylactic effect of calcium channel blockers against oxaliplatin‐induced acute peripheral neuropathy (1143.8)

Abstract

Although oxaliplatin (L‐OHP) is an important anticancer agent against colorectal cancer, severe acute and chronic peripheral neuropathies are frequently occurred. We peviously reported that oxalate derived from L‐OHP is involved in acute cold hyperalgesia. In the present study, the mechanism of L‐OHP‐induced acute neuropathy was examined with the effects of calcium channel blockers in the rat model and primary cultured dorsal root ganglia (DRG). Administration of L‐OHP or oxalate to rats induced cold hyperalgesia, and increased in transient receptor potential melastatin 8 (TRPM8) mRNA levels in DRG. In addition, the treatment of L‐OHP or oxalate induced Ca²⁺ influx and nuclear factor of activated T‐cell (NFAT) nuclear translocation as well as up‐regulation of the TRPM8 mRNA levels in cultured DRG. These oxalate‐induced changes were inhibited by nifedipine, diltiazem and mexiletine. Comparable to the in vitro results, administration of these calcium channel blockers prevented the L‐OHP‐induced cold hyperalgesia in rats. These results suggest that the L type calcium channels/NFAT/TRPM8 pathway is a downstream mediator for L‐OHP‐induced cold hyperalgesia, and that calcium channel blockers may have prophylactic potential against L‐OHP‐induced acute neuropathy.