mprovements in chemotherapy have increased the cancer patient's life span, but these drugs produce severe side-effects, including a sensory neuropathy that is often accompanied by a chronic neuropathic pain syndrome. There are no proven treatments to prevent the neuropathy per se or the pain syndrome, and the pain is resistant to standard analgesics. Chemotherapeutics in the taxane class are among the most effective drugs for the treatment of solid tumors, but they are also most often associated with a painful peripheral neuropathy. The cause of the pain is not known. Chemotherapy-evoked painful peripheral neuropathy affects tens of thousands of patients. For some, it compromises or prevents aggressive use of therapy with life-saving anti-tumor activity; for others it contributes to a serious decrease in the quality of life. There is evidence that the mechanisms that produce chemotherapy-evoked neuropathic pain are distinctly different than those found in models of post-traumatic painful peripheral neuropathy. Thus, the research proposed here addresses a pressing clinical problem and also has the potential to increase our understanding of neuropathic pain mechanisms in general. It is now possible to reproduce the painful peripheral neuropathy in rats receiving the taxane drug, paclitaxel (Taxol). The animals have long-lasting mechano-hyperalgesia, mechano-allodynia, and cold-allodynia, but little or no heat-hyperalgesia. The goal of the research proposed here is to discover the cause of the pain. We propose studies to confirm and extend our preliminary observations, including: (1) a quantitative time-course electron-microscopy study to confirm the absence of A- or C-fiber degeneration, and to confirm that both fiber types contain a significantly increased number of abnormal mitochondria; (2) quantitative immunocytochemical studies to confirm that the density of the cutaneous innervation is not altered; (3) electrophysiological studies to confirm that there is an abnormal spontaneous discharge in primary afferent A-delta and C-fibers; (4) dose-response studies using anti-oxidant therapies and intrathecally administered calcium chelators to confirm their analgesic efficacy, consistent with the presence of increased free radicals and dysregulation of calcium homeostasis due to mitochondrial dysfunction; and (5) direct tests of the hypothesis that oxidative stress and calcium dysregulation generate sponanteous afferent discharge. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS052255-02
Application #
7231959
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Porter, Linda L
Project Start
2006-05-10
Project End
2010-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
2
Fiscal Year
2007
Total Cost
$188,762
Indirect Cost
Name
Mcgill University
Department
Type
DUNS #
205667090
City
Montreal
State
PQ
Country
Canada
Zip Code
H3 0-G4
Xiao, Wen Hua; Bennett, Gary J (2012) Effects of mitochondrial poisons on the neuropathic pain produced by the chemotherapeutic agents, paclitaxel and oxaliplatin. Pain 153:704-9
Zheng, H; Xiao, W H; Bennett, G J (2012) Mitotoxicity and bortezomib-induced chronic painful peripheral neuropathy. Exp Neurol 238:225-34
Xiao, W H; Zheng, H; Bennett, G J (2012) Characterization of oxaliplatin-induced chronic painful peripheral neuropathy in the rat and comparison with the neuropathy induced by paclitaxel. Neuroscience 203:194-206
Zheng, Huaien; Xiao, Wen Hua; Bennett, Gary J (2011) Functional deficits in peripheral nerve mitochondria in rats with paclitaxel- and oxaliplatin-evoked painful peripheral neuropathy. Exp Neurol 232:154-61
Bennett, Gary J; Liu, Guo K; Xiao, Wen H et al. (2011) Terminal arbor degeneration--a novel lesion produced by the antineoplastic agent paclitaxel. Eur J Neurosci 33:1667-76
Xiao, W H; Zheng, H; Zheng, F Y et al. (2011) Mitochondrial abnormality in sensory, but not motor, axons in paclitaxel-evoked painful peripheral neuropathy in the rat. Neuroscience 199:461-9
Zheng, F Y; Xiao, W-H; Bennett, G J (2011) The response of spinal microglia to chemotherapy-evoked painful peripheral neuropathies is distinct from that evoked by traumatic nerve injuries. Neuroscience 176:447-54
Bennett, Gary J (2010) Pathophysiology and animal models of cancer-related painful peripheral neuropathy. Oncologist 15 Suppl 2:9-12
Xiao, Wen Hua; Zheng, Felix Y; Bennett, Gary J et al. (2009) Olesoxime (cholest-4-en-3-one, oxime): analgesic and neuroprotective effects in a rat model of painful peripheral neuropathy produced by the chemotherapeutic agent, paclitaxel. Pain 147:202-9
Xiao, Wen Hua; Bennett, Gary J (2008) Chemotherapy-evoked neuropathic pain: Abnormal spontaneous discharge in A-fiber and C-fiber primary afferent neurons and its suppression by acetyl-L-carnitine. Pain 135:262-70

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