Oxaliplatin acts on IB4-positive nociceptors to induce an oxidative stress-dependent acute painful peripheral neuropathy.
The toxicity profile of oxaliplatin, a platinum derivative currently used in the treatment of colorectal cancer, differs from those of the other platinum compounds, cisplatin and carboplatin. Oxaliplatin treatment induces an acute neurotoxicity characterized by a rapid onset of cold-induced distal dysesthesia and a chronic sensory peripheral neuropathy. A single intravenous dose of oxaliplatin produced a dose-dependent mechanical hyperalgesia and heat and cold allodynia; repeated administration intensified symptoms. A single intradermal dose of oxaliplatin produced a dose-dependent mechanical hyperalgesia. A single dose intravenous oxaliplatin also lowered thresholds and increased responses of C-fiber nociceptors to mechanical stimulation, confirming a peripheral site of action. Whereas peripheral administration of inhibitors of second messengers implicated in models of other painful peripheral neuropathies (PKA, PKC, NO, Ca(2+), and caspase) had no effect; both systemic and local administration of antioxidants (acetyl-L-carnitine, alpha-lipoic acid or vitamin C), all markedly inhibited oxaliplatin-induced hyperalgesia. Intrathecal administration of the neurotoxin for IB4-positive nociceptors, IB4-saporin, markedly attenuated IB4 staining in the dorsal horn of the spinal cord and completely prevented oxaliplatin-induced hyperalgesia. We suggest that oxaliplatin acts on IB4 (+)-nociceptors to induce oxidative stress-dependent acute peripheral sensory neuropathy.


CONCLUSIONS
Many drugs used to treat cancer produce pain as their dose-limiting side effect. We used a model of this pain syndrome induced by oxaliplatin to demonstrate that pain is produced by action on a subset of nociceptors, the IB4-positive DRG neurons. This information could help define cellular targets against which protective therapies could be developed.
Joseph
Elizabeth K
EK
Department of Medicine, Division of Neuroscience, University of California, San Francisco, San Francisco, California 94143-0440, USA. Elizabeth.Joseph@ucsf.edu
Chen
Xiaojie
X
Bogen
Oliver
O
Levine
Jon D
JD
D000208:Acute Disease; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D037102:Lectins / Q000494:pharmacology; D008297:Male; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000502:physiology; D009437:Neuralgia / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000633:toxicity*; D000077150:Oxaliplatin; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D037121:Plant Lectins; D051381:Rats; D054789:Ribosome Inactivating Proteins, Type 1 / Q000494:pharmacology; D000076985:Saporins; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D013194:Staining and Labeling
D000970:Antineoplastic Agents; D000975:Antioxidants; C045475:Griffonia simplicifolia lectins; C496198:IB4-saporin conjugate; D037102:Lectins; D009944:Organoplatinum Compounds; D037121:Plant Lectins; D054789:Ribosome Inactivating Proteins, Type 1; D000077150:Oxaliplatin; D000076985:Saporins