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Targeting Nerve Growth Factor in Pain

What is the Therapeutic Potential?

  • Mechanisms and Targets
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Abstract

Chronic pain presents a huge economic and social burden, with existing treatments largely unable to satisfy medical needs. Recently, studies have shown that nerve growth factor (NGF) is a major mediator of inflammatory and neuropathic pain, providing a new therapeutic target. Although originally discovered as a trophic factor for sympathetic and sensory neurons during development, it now appears that in adults, levels of NGF are elevated in many acute and chronic pain conditions. Furthermore, preclinical animal models of inflammatory and neuropathic pain also show increased NGF levels, while the sequestration of NGF alleviates the associated hyperalgesia. The molecular mechanisms involved are being elucidated.

This review briefly examines pain signaling pathways and describes currently available analgesics. It then investigates the approaches taken in targeting NGF-mediated pain. Current options being explored include the development of humanized monoclonal antibodies to NGF or its tyrosine kinase receptor TrkA (also known as neurotrophic tyrosine kinase receptor, type 1 [NTRK1]), and the sequestration of NGF using TrkA domain 5 (TrkAd5), a soluble receptor protein that binds NGF with picomolar affinity. Administration of either antibodies or TrkAd5 has been shown to be effective in a number of preclinical models of pain, including cystitis, osteoarthritis, UV irradiation (sunburn), and skeletal bone pain due to fracture or cancer. Other possible future therapies examined in this review include small-molecule TrkA antagonists, which target either the extracellular NGF binding domain of TrkA or its intracellular tyrosine kinase domain.

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Acknowledgments

Judy Watson is funded by Bristol Research into Alzheimer’s and Care of the Elderly. Shelley Allen is a Sigmund Gestetner Senior Research Fellow. David Dawbarn and Shelley Allen are inventors on University of Bristol patents involving TrkAd5 (TrkAIg2).

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  1. University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK

    Judy J. Watson, Shelley J. Allen & DrDavid Dawbarn

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Watson, J.J., Allen, S.J. & Dawbarn, D. Targeting Nerve Growth Factor in Pain. BioDrugs 22, 349–359 (2008). https://doi.org/10.2165/0063030-200822060-00002

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