Targeting Nerve Growth Factor in Pain

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.

Effect of orexin-A (hypocretin-1) on hyperalgesic and cachectic manifestations of experimentally induced rheumatoid arthritis in rats

“…The findings from our study are supported by Watson et al 2008, who reported that NGF is a major mediator of inflammatory and neuropathic pain by binding to high-affinity tyrosine kinase receptor A, and preclinical animal models of inflammatory pain also show increased NGF levels. Furthermore, Capsoni et al 2011 stated that the relationship between NGF and pain is supported by genetic evidence; that mutations in the NGF receptors in patients affected by a hereditary rare disease (Hereditary Sensory and Autonomic Neuropathy type IV, HSAN IV) determine a congenital form of severe pain insensitivity and mental retardation.…”

Mechanisms of nerve growth factor signaling in bone nociceptors and in an animal model of inflammatory bone pain

“…3,38,41–43,98,99 NGF sequestration has been successfully applied in clinical trials to treat osteoarthritic pain. 100–104 While there have been some concerns about safety, the benefits for pain management are clear.…”

“…2,3 NGF acts through two cell surface receptors: p75 and TrkA. Mutations of TrkA genes have been reported in individuals who have congenital insensitivity to pain.…”

Chronic Social Stress Time-Dependently Affects Neuropathic Pain-Related Cold Allodynia and Leads to Altered Expression of Spinal Biochemical Mediators

“…On the other hand it has recently been shown that corticosterone may also mediate analgesia via the spinal production of neuroactive metabolites that enhance GABAergic inhibitory transmission (Zell et al, 2015). With regard to neurotrophic factors, stress-induced release of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) is involved in the neurobiological alterations underlying increased vulnerability to disease in humans (Cirulli and Alleva, 2009); but NGF is also a critical mediator for the enhancement and maintenance of inflammatory (Woolf et al, 1994; Watson et al, 2008) and neuropathic pain (Santos et al, 2012). Recently, dynamic epigenetic regulations of the glial cell line-derived neurotrophic factor (GDNF) promoter in the nucleus accumbens (NAc) also have been shown to play important roles in determining both the susceptibility and the adaptation responses to chronic stressful events (Uchida et al, 2011).…”