Novel class of pain drugs based on antagonism of NGF

Hefti, Franz; Rosenthal, Arnon; Walicke, Patricia A.; Wyatt, Sean; Vergara, G.; Shelton, David L.; Davies, Alun M.

doi:10.1016/j.tips.2005.12.001

Cited by 344 publications

(287 citation statements)

References 66 publications

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“…Mitogen-activated protein kinases, activated by TrkA kinase activity, are retrogradely transported in signaling endosomes containing phosphorylated TrkA and NGF is transported to DRG neuronal cell bodies after NGF stimulation (4) and enhance the expression of several proteins associated with central sensitization of inflammatory pain, such as TRPV1 (1). Increased TrkA activity stimulated by NGF augments expression of TRPV1 in DRG neurons and PC12 cells (5).…”

Section: Discussionmentioning

confidence: 99%

“…Nerve growth factor (NGF) plays pivotal roles in inflammatory pain (1). Single injection of NGF either systemically or locally induces persistent thermal hyperalgesia in rodents (2).…”

Section: Introductionmentioning

confidence: 99%

“…After NGF binds to TrkA, NGF signaling containing NGF, TrkA, and activated signaling proteins is transmitted retrogradely through axonal transport of TrkA from the peripheral terminals of nociceptive neurons to the cell bodies of the dorsal root ganglion (DRG) (4). In several persistent pain states, NGF sensitizes transient receptor potential channel 1 (TRPV1) in nerve terminals, and retrograde transport of TrkA to DRG neurons activates mitogen-activated protein kinases and enhances expres-sion of several proteins (e.g., substance P, tetrodotoxinresistant voltage-gated sodium channel Nav1.8, TRPV1 channel, brain-derived neurotrophic factor) in DRG neurons with modulation of spinal N-methyl-D-aspartate receptors (1,2,5).…”

Section: Introductionmentioning

confidence: 99%

“…Under the severe inflammatory pain state in which neither non-steroidal anti-inflammatory drugs nor opiate drugs have any therapeutic effect, novel agents to antagonize NGF are required because the dominant role of NGF as a pain mediator is recognized (1). Although anti-NGF antibody (6) and TrkAd5, which binds NGF (7), are effective for several models of the pain state, repetitive administration is required to suppress the long-lasting pain state, as interaction with NGF occurs primarily at extracellular sites.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Synthetic Cell-Penetrating Peptides on TrkA Activity in PC12 Cells

et al. 2008

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Abstract. As TrkA, a high-affinity receptor of nerve growth factor (NGF), is a potential target for relieving uncontrolled inflammatory pain, an effective inhibitor of TrkA has been required for pain management. To identify a specific inhibitor of TrkA activity, we designed cell-penetrating peptides combined with amino-acid sequences in the activation loop of TrkA to antagonize tyrosine kinase activity. To select a peptide inhibiting TrkA activity, we examined the effect of cell-penetrating peptides on tyrosine kinase activity of recombinant TrkA in vitro and studied their effects on NGF-stimulated neurite outgrowth and protein phosphorylation in PC12 cells. Thereafter we investigated the effect of the selected peptide on NGF-stimulated TrkA activity and the expression of transient receptor potential channel 1 in PC12 cells. The selected peptide inhibited TrkA activity, but did not inhibit tyrosine kinase activities of other receptor-type tyrosine kinases in vitro. It also suppressed NGF-stimulated responses in PC12 cells. The selected synthetic cell-penetrating peptide antagonizing TrkA function would be a candidate for inflammatory pain therapy.

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Section: Discussionmentioning

confidence: 99%

“…Nerve growth factor (NGF) plays pivotal roles in inflammatory pain (1). Single injection of NGF either systemically or locally induces persistent thermal hyperalgesia in rodents (2).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of Synthetic Cell-Penetrating Peptides on TrkA Activity in PC12 Cells

et al. 2008

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“…63 In contrast to BDNF and NGF, GDNF appears to have generally beneficial effects in animal models of nerve injury-induced painful neuropathy, without producing hyper or hypoalgesia in naïve animals. The GDNF family of trophic factors and their receptors (the receptor tyrosine kinase RET in combination with a family of GPI-linked coreceptors) are widely expressed in the central and peripheral nervous system.…”

Section: Neurodegeneration: Mechanisms and Possible Targets Trophic Facmentioning

confidence: 99%

Targeting Neuroprotection as an Alternative Approach to Preventing and Treating Neuropathic Pain

Bordet

Pruss

2009

Neurotherapeutics

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Summary:Neuropathic pain syndromes arise from dysfunction of the nerve itself, through traumatic or nontraumatic injury. Unlike acute pain syndromes, the pain is long-lasting and does not respond to common analgesic therapies. Drugs that disrupt nerve conduction and transmission or central sensitization, currently the only effective treatments, are only modestly effective for a portion of the patients suffering from neuropathic pain and come with the cost of serious adverse effects. Neurodegeneration, as a reaction to nerve trauma or chronic metabolic or chemical intoxication, appears to be an underlying cause of neuropathic pain. Identifying mechanisms of neurodegeneration and designing neuroprotective therapies is an ambitious goal toward treating or even preventing the development of these disabling disorders.

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