Comparison of oxaliplatin- and cisplatin-induced painful peripheral neuropathy in the rat

Abstract

Although platinum-based cancer chemotherapies produce painful peripheral neuropathy as dose-limiting side effects, there are important differences in the pain syndromes produced by members of this class of drugs. In the rat, cisplatin-induced hyperalgesia has latency to onset of 24 to 48 hours, is maximal by 72 to 96 hours, and is attenuated by inhibitors of caspase signaling but not by inhibitors of the mitochondrial electron transport chain (mETC) and antioxidants. In contrast, oxaliplatin-induced mechanical hyperalgesia is already present by 5 minutes and peaks by 20 minutes. Whereas oxaliplatin hyperalgesia persists for weeks, starting around day 10 to 15, its severity decreases to a lower 2nd plateau level. The rapid-onset 1st plateau in oxaliplatin-induced hyperalgesia was characterized by prominent cold allodynia and in contrast to cisplatin was attenuated by inhibitors of the mETC and antioxidants but not inhibitors of caspase signaling. However, tested later during the 2nd plateau, it was characterized by less intense hyperalgesia and no cold allodynia and was attenuated by inhibitors of caspase signaling as well as by inhibitors of the mETC and by antioxidants.

Perspective: The findings of this study distinguish between the neuropathic pain syndromes produced by members of a single chemical class of anticancer drugs and suggest that the underlying mechanisms of various forms of peripheral neuropathy may be different. Further, it defines the need for selective therapy for different types of neuropathy.

Figure 1

A. Time course of Oxaliplatin (0.5 mg/kg, i.v. reported from to show the two plateau of Oxaliplatin hyperalgesia, and 2 mg/kg, i.v., n =12/group) and Cisplatin (2 mg/kg/i.v. n = 6/group) induced mechanical hyperalgesia. Oxaliplatin (2 mg/kg, i.v.) induced hyperalgesia lasted over 6 weeks and on the 42^nd day there still was significant (p<0.01) hyperalgesia, while Cisplatin hyperalgesia lasted less than 2 weeks. Also there was a significant difference in the intensity of Oxaliplatin (2 mg/kg, i.v.) hyperalgesia between day 5 and day 20 (p<0.01). B. Onset of mechanical hyperalgesia induced by Oxaliplatin and Cisplatin (both 2 mg/kg/i.v. n = 6/group). Oxaliplatin induced hyperalgesia has markedly faster onset than Cisplatin hyperalgesia.

Figure 2

A. Mechanical allodynia induced by Oxaliplatin (1^st and 2^nd plateau) and Cisplatin (n = 6/group). B. Effect of Oxaliplatin (1^st and 2^nd plateau) and Cisplatin (n = 6/group) on response to noxious heat, measured by Hargreaves test, and C. Effect of Oxaliplatin (1^st and 2^nd plateau) and Cisplatin (n = 6/group), on response to noxious cold (10°C). The level of significance is denoted by (*) where p<0.05 = *, p<0.01 = ** and p<0.001 = ***. OXP = Oxaliplatin, CISP = Cisplatin.

Figure 3

Effect of mitochondrial electron transport complex (mETC) inhibitors rotenone, 3-NP, antimycin, sodium cyanide and oligomycin, antioxidants acetyl-L-carnitine (ALC), a-lipoic acid (a-lipo) and vitamin C, and a caspase inhibitor (ZVAD-FMK) on the A. acute, and B. chronic effect of Oxaliplatin-induced mechanical hyperalgesia, and C. on Cisplatin-induced mechanical hyperalgesia (n=6/group). All inhibitors were administered to different groups of Oxaliplatin and Cisplatin treated rats.