Administration of a Tropomyosin Receptor Kinase Inhibitor Attenuates Sarcoma-Induced Nerve Sprouting, Neuroma Formation and Bone Cancer Pain
Open Access
- 1 January 2010
- journal article
- Published by SAGE Publications in Molecular Pain
- Vol. 6, 87
- https://doi.org/10.1186/1744-8069-6-87
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.Keywords
This publication has 44 references indexed in Scilit:
- Sustained blockade of neurotrophin receptors TrkA, TrkB and TrkC reduces non-malignant skeletal pain but not the maintenance of sensory and sympathetic nerve fibersBone, 2011
- Blockade of nerve sprouting and neuroma formation markedly attenuates the development of late stage cancer painNeuroscience, 2010
- A phenotypically restricted set of primary afferent nerve fibers innervate the bone versus skin: Therapeutic opportunity for treating skeletal painBone, 2010
- Cellular and Molecular Mechanisms of PainCell, 2009
- Treating skeletal pain: limitations of conventional anti-inflammatory drugs, and anti-neurotrophic factor as a possible alternativeNature Clinical Practice Rheumatology, 2009
- Intravenous Ibandronate Rapidly Reduces Pain, Neurochemical Indices of Central Sensitization, Tumor Burden, and Skeletal Destruction in a Mouse Model of Bone CancerJournal of Pain and Symptom Management, 2008
- The Degenerated Lumbar Intervertebral Disc is Innervated Primarily by Peptide-Containing Sensory Nerve Fibers in HumansSpine, 2006
- Primary afferent nociceptor mechanisms mediating NGF‐induced mechanical hyperalgesiaEuropean Journal of Neuroscience, 2005
- Spontaneous discharge of afferents in a neuroma reflects original receptor tuningBrain Research, 1990
- Axoplasmic transport block reduces ectopic impulse generation in injured peripheral nervesPain, 1983