Blockade of nerve sprouting and neuroma formation markedly attenuates the development of late stage cancer pain

W. G. Mantyh, J. M. Jimenez-Andrade, J. I. Stake, A. P. Bloom, M. J. Kaczmarska, R. N. Taylor, K. T. Freeman, J. R. Ghilardi, M. A. Kuskowski, P. W. Mantyh

Research output: Contribution to journalArticlepeer-review

114 Scopus citations

Abstract

For many patients, pain is the first sign of cancer and, while pain can be present at any time, the frequency and intensity of pain tend to increase with advancing stages of the disease. Thus, between 75 and 90% of patients with metastatic or advanced-stage cancer will experience significant cancer-induced pain. One major unanswered question is why cancer pain increases and frequently becomes more difficult to fully control with disease progression. To gain insight into this question we used a mouse model of bone cancer pain to demonstrate that as tumor growth progresses within bone, tropomyosin receptor kinase A (TrkA)-expressing sensory and sympathetic nerve fibers undergo profuse sprouting and form neuroma-like structures. To address what is driving the pathological nerve reorganization we administered an antibody to nerve growth factor (anti-NGF). Early sustained administration of anti-NGF, whose cognate receptor is TrkA, blocks the pathological sprouting of sensory and sympathetic nerve fibers, the formation of neuroma-like structures, and inhibits the development of cancer pain. These results suggest that cancer cells and their associated stromal cells release nerve growth factor (NGF), which induces a pathological remodeling of sensory and sympathetic nerve fibers. This pathological remodeling of the peripheral nervous system then participates in driving cancer pain. Similar to therapies that target the cancer itself, the data presented here suggest that, the earlier therapies blocking this pathological nerve remodeling are initiated, the more effective the control of cancer pain.

Original languageEnglish (US)
Pages (from-to)588-598
Number of pages11
JournalNeuroscience
Volume171
Issue number2
DOIs
StatePublished - Dec 1 2010

Bibliographical note

Funding Information:
We thank Marvin Landis and the University of Arizona Information Technology Service for generating the 3D renderings of the innervated bone. This work was supported by the National Institutes of Health grant ( NS23970 ), by the Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service Grants ( O4380-I and A6707-R ) and by the Calhoun Fund for Bone Pain.

Keywords

  • Breakthrough pain
  • Periosteum
  • Preventive analgesia

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