Administration of a tropomyosin receptor kinase inhibitor attenuates sarcoma-induced nerve sprouting, neuroma formation and bone cancer pain

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Abstract

Pain often accompanies cancer and most current therapies for treating cancer pain have significant unwanted side effects. Targeting nerve growth factor (NGF) or its cognate receptor tropomyosin receptor kinase A (TrkA) has become an attractive target for attenuating chronic pain.

In the present report, we use a mouse model of bone cancer pain and examine whether oral administration of a selective small molecule Trk inhibitor (ARRY-470, which blocks TrkA, TrkB and TrkC kinase activity at low nm concentrations) has a significant effect on cancer-induced pain behaviors, tumor-induced remodeling of sensory nerve fibers, tumor growth and tumor-induced bone remodeling. Early/sustained (initiated day 6 post cancer cell injection), but not late/acute (initiated day 18 post cancer cell injection) administration of ARRY-470 markedly attenuated bone cancer pain and significantly blocked the ectopic sprouting of sensory nerve fibers and the formation of neuroma-like structures in the tumor bearing bone, but did not have a significant effect on tumor growth or bone remodeling.

These data suggest that, like therapies that target the cancer itself, the earlier that the blockade of TrkA occurs, the more effective the control of cancer pain and the tumor-induced remodeling of sensory nerve fibers. Developing targeted therapies that relieve cancer pain without the side effects of current analgesics has the potential to significantly improve the quality of life and functional status of cancer patients.

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Distinct expression of TRPM8, TRPA1, and TRPV1 mRNAs in rat primary afferent neurons with adelta/c-fibers and colocalization with trk receptors.

Kimiko Kobayashi, Tetsuo Fukuoka, Koichi Obata … (2005)

The transient receptor potential (TRP) superfamily of cation channels contains four temperature-sensitive channels, named TRPV1-4, that are activated by heat stimuli from warm to that in the noxious range. Recently, two other members of this superfamily, TRPA1 and TRPM8, have been cloned and characterized as possible candidates for cold transducers in primary afferent neurons. Using in situ hybridization histochemistry and immunohistochemistry, we characterized the precise distribution of TRPA1, TRPM8, and TRPV1 mRNAs in the rat dorsal root ganglion (DRG) and trigeminal ganglion (TG) neurons. In the DRG, TRPM8 mRNA was not expressed in the TRPV1-expressing neuronal population, whereas TRPA1 mRNA was only seen in some neurons in this population. Both A-fiber and C-fiber neurons expressed TRPM8, whereas TRPV1 was almost exclusively seen in C-fiber neurons. All TRPM8-expressing neurons also expressed TrkA, whereas the expression of TRPV1 and TRPA1 was independent of TrkA expression. None of these three TRP channels were coexpressed with TrkB or TrkC. The TRPM8-expressing neurons were more abundant in the TG compared with the DRG, especially in the mandibular nerve region innervating the tongue. Our data suggest heterogeneity of TRPM8 and TRPA1 expression by subpopulations of primary afferent neurons, which may result in the difference of cold-sensitive primary afferent neurons in sensitivity to chemicals such as menthol and capsaicin and nerve growth factor. Copyright (c) 2005 Wiley-Liss, Inc.

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Malignant bone pain: pathophysiology and treatment.

S Mercadante (1996)

The presence of bone metastases predicts the presence of pain and is the most common cause of cancer-related pain. Although bone metastases do not involve vital organs, they may determine deleterious effects in patients with prolonged survival. Bone fractures, hypercalcaemia, neurologic deficits and reduced activity associated with bone metastases result in an overall compromise in the patient's quality of life. A metastasis is a consequence of a cascade of events including a progressive growth at the primary site, vascularization phase, invasion, detachment, embolization, survival in the circulation, arrest at the site of a metastasis, extravasion, evasion of host defense and progressive growth. Once cancer cells establish in the bone, the normal process of bone turnover is disturbed. The different mechanisms responsible for osteoclast activation correspond to typical radiologic features showing lytic, sclerotic or mixed metastases, according to the primary tumor. The release of chemical mediators, the increased pressure within the bone, microfractures, the stretching of periosteum, reactive muscle spasm, nerve root infiltration and compression of nerves by the collapse of vertebrae are the possible mechanisms of malignant bone pain. Pain is often disproportionate to the size or degree of bone involvement. A comprehensive assessment including a trusting relationship with the patient, taking a careful history of the pain complaint, the characteristics of the pain, the evaluation of the psychological status of the patient, neurological examination, the reviewing of diagnostic studies and laboratory findings, and individualization of the therapeutic approach, should precede any treatment. Radiotherapy is the cornerstone of the treatment. Low doses given in a single session are safe and effective, and reduce distress and inconvenience associated with repeated session. Radioisotopes are more imprecise in delivering specific doses of radiation, but have less toxicity and easy administration as well as effectiveness in subclinical sites of metastases, although storage, dispensing and administration should be under strict control. Chemotherapy and endocrine therapy are difficult to measure in terms of pain relief. Prophylactic fixation surgery can lead to improved survival and quality of life of patients with bone metastases. Surgical treatment should be undertaken when fracture occurs. Careful selection of patients for surgical spinal decompression is required. The potential benefits of surgical interventions have to be tempered with patient survival. The use of analgesics according to the WHO ladder is recommended. There is no clear evidence that non-steroidal anti-inflammatory drugs (NSAIDs) have a specific efficacy in malignant bone pain. The difficulty with incident pain is not a lack of response to systemic opioids, but rather that the doses required to control the incidental pain produce unacceptable side-effects at rest. Alternative measures are often required. The inhibition of bone resorption and hypercalcaemia can be reduced by the use of bisphosphonates. This class of drugs potentiate the effects of analgesics in improving metastatic bone pain. Invasive techniques are rarely indicated, but may provide analgesia in the treatment of pain resistant to the other modalities. Neural blockade should never be used as the sole modality for malignant bone pain, but should be considered as a helpful in specific pain situations. Careful appraisal and the application of a correct approach should enable the patient with bone metastases to obtain an acceptable pain relief despite the advanced nature of their malignant disease.

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Brain-derived neurotrophic factor modulates nociceptive sensory inputs and NMDA-evoked responses in the rat spinal cord.

B J Kerr, E. J. Bradbury, D L H Bennett … (1999)

Central sensitization, the hyperexcitability of spinal processing that often accompanies peripheral injury, is a major component of many persistent pain states. Here we report that the neurotrophin, brain-derived neurotrophic factor (BDNF), is a modulator of excitability within the spinal cord and contributes to the mechanism of central sensitization. BDNF, localized in primary sensory neuron cell bodies and central terminals, potentiates nociceptive spinal reflex responses in an in vitro spinal cord preparation and induces c-fos expression in dorsal horn neurons. NMDA receptor-mediated responses, known as a major contributor to central sensitization, were significantly enhanced by exogenous BDNF. Systemic NGF treatment, a procedure that mimics peripheral inflammatory states, raises BDNF levels in sensory neurons and increases nociceptive spinal reflex excitability. This increased central excitability is reduced by trkB-IgG, a BDNF "antagonist." We also show directly that inflammatory pain-related behavior depends on BDNF release in vivo. Thus behavioral nociceptive responses induced by intraplantar formalin and by intraplantar carageenan are significantly attenuated by trkB-IgG. Hence BDNF is appropriately localized and regulated in inflammatory states and is sufficient and necessary for the expression of central sensitization in the spinal cord. We propose that BDNF may function as a modulator of central sensitization in pathological states, and our results suggest that pharmacological antagonism of BDNF may prove an effective and novel analgesic strategy for the treatment of persistent inflammatory pain states.

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Author and article information

Journal

Journal ID (nlm-ta): Mol Pain

Title: Molecular Pain

Publisher: BioMed Central

ISSN (Electronic): 1744-8069

Publication date Collection: 2010

Publication date (Electronic): 7 December 2010

Volume: 6

Page: 87

Affiliations

[1 ]Research Service, VA Medical Center, One Veterans Drive, Minneapolis, MN 55417, USA

[2 ]Department of Pharmacology, University of Arizona, 1656 E. Mabel, Tucson, AZ 85724, USA

[3 ]GRECC, VA Medical Center, One Veterans Drive, Minneapolis, MN 55417, USA

[4 ]Arizona Cancer Center, University of Arizona, 1656 E. Mabel, Tucson, AZ 85724, USA

Article

Publisher ID: 1744-8069-6-87

DOI: 10.1186/1744-8069-6-87

PMC ID: 3004846

PubMed ID: 21138586

SO-VID: 0e13cfaf-e874-468b-a334-bc01dec7bceb

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<url>http://creativecommons.org/licenses/by/2.0</url>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Administration of a tropomyosin receptor kinase inhibitor attenuates sarcoma-induced nerve sprouting, neuroma formation and bone cancer pain

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Most cited references 35

Distinct expression of TRPM8, TRPA1, and TRPV1 mRNAs in rat primary afferent neurons with adelta/c-fibers and colocalization with trk receptors.

Malignant bone pain: pathophysiology and treatment.

Brain-derived neurotrophic factor modulates nociceptive sensory inputs and NMDA-evoked responses in the rat spinal cord.

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