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Oxaliplatin acts on IB4-positive nociceptors to induce an oxidative stress-dependent acute painful peripheral neuropathy.
J Pain. 2008 May; 9(5):463-72.JP

Abstract

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.

Authors+Show Affiliations

Department of Medicine, Division of Neuroscience, University of California, San Francisco, San Francisco, California 94143-0440, USA. Elizabeth.Joseph@ucsf.eduNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

18359667

Citation

Joseph, Elizabeth K., et al. "Oxaliplatin Acts On IB4-positive Nociceptors to Induce an Oxidative Stress-dependent Acute Painful Peripheral Neuropathy." The Journal of Pain : Official Journal of the American Pain Society, vol. 9, no. 5, 2008, pp. 463-72.
Joseph EK, Chen X, Bogen O, et al. Oxaliplatin acts on IB4-positive nociceptors to induce an oxidative stress-dependent acute painful peripheral neuropathy. J Pain. 2008;9(5):463-72.
Joseph, E. K., Chen, X., Bogen, O., & Levine, J. D. (2008). Oxaliplatin acts on IB4-positive nociceptors to induce an oxidative stress-dependent acute painful peripheral neuropathy. The Journal of Pain : Official Journal of the American Pain Society, 9(5), 463-72. https://doi.org/10.1016/j.jpain.2008.01.335
Joseph EK, et al. Oxaliplatin Acts On IB4-positive Nociceptors to Induce an Oxidative Stress-dependent Acute Painful Peripheral Neuropathy. J Pain. 2008;9(5):463-72. PubMed PMID: 18359667.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Oxaliplatin acts on IB4-positive nociceptors to induce an oxidative stress-dependent acute painful peripheral neuropathy. AU - Joseph,Elizabeth K, AU - Chen,Xiaojie, AU - Bogen,Oliver, AU - Levine,Jon D, Y1 - 2008/03/24/ PY - 2007/12/04/received PY - 2008/01/22/revised PY - 2008/01/24/accepted PY - 2008/3/25/pubmed PY - 2008/8/1/medline PY - 2008/3/25/entrez SP - 463 EP - 72 JF - The journal of pain : official journal of the American Pain Society JO - J Pain VL - 9 IS - 5 N2 - UNLABELLED: 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. SN - 1526-5900 UR - https://www.unboundmedicine.com/medline/citation/18359667/Oxaliplatin_acts_on_IB4_positive_nociceptors_to_induce_an_oxidative_stress_dependent_acute_painful_peripheral_neuropathy_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1526-5900(08)00389-1 DB - PRIME DP - Unbound Medicine ER -