Oxaliplatin acts on IB4-positive nociceptors to induce an oxidative stress-dependent acute painful peripheral neuropathy

J Pain. 2008 May;9(5):463-72. doi: 10.1016/j.jpain.2008.01.335. Epub 2008 Mar 24.


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.

Perspective: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Disease
  • Animals
  • Antineoplastic Agents / toxicity
  • Antioxidants / pharmacology
  • Antioxidants / therapeutic use
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Hyperalgesia / chemically induced
  • Hyperalgesia / metabolism
  • Hyperalgesia / physiopathology
  • Injections, Intravenous
  • Injections, Subcutaneous
  • Lectins / pharmacology
  • Male
  • Nerve Fibers, Unmyelinated / drug effects
  • Nerve Fibers, Unmyelinated / physiology
  • Neuralgia / chemically induced*
  • Neuralgia / metabolism
  • Neuralgia / physiopathology
  • Nociceptors / drug effects*
  • Nociceptors / metabolism
  • Organoplatinum Compounds / toxicity*
  • Oxaliplatin
  • Oxidative Stress / drug effects*
  • Oxidative Stress / physiology
  • Pain Threshold / drug effects
  • Pain Threshold / physiology
  • Peripheral Nervous System Diseases / chemically induced*
  • Peripheral Nervous System Diseases / metabolism
  • Peripheral Nervous System Diseases / physiopathology
  • Plant Lectins
  • Rats
  • Ribosome Inactivating Proteins, Type 1 / pharmacology
  • Saporins
  • Sensory Receptor Cells / drug effects*
  • Sensory Receptor Cells / metabolism
  • Sensory Receptor Cells / physiopathology
  • Staining and Labeling


  • Antineoplastic Agents
  • Antioxidants
  • Griffonia simplicifolia lectins
  • IB4-saporin conjugate
  • Lectins
  • Organoplatinum Compounds
  • Plant Lectins
  • Ribosome Inactivating Proteins, Type 1
  • Oxaliplatin
  • Saporins