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


CONCLUSIONS
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.
Joseph
Elizabeth K
EK
Department of Oral and Maxillofacial Surgery and Division of Neuroscience, University of California at San Francisco, San Francisco, CA 94143-0440, USA. Elizabeth.Joseph@ucsf.edu
Levine
Jon D
JD
D000818:Animals; D000970:Antineoplastic Agents; D001522:Behavior, Animal / Q000187:drug effects; D020169:Caspases / Q000502:physiology; D002945:Cisplatin; D003080:Cold Temperature; D004305:Dose-Response Relationship, Drug; D004579:Electron Transport / Q000187:drug effects; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced / Q000523:psychology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010146:Pain / Q000139:chemically induced*; D010147:Pain Measurement / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced*; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015290:Second Messenger Systems / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D020169:Caspases; D002945:Cisplatin