A possible role for nerve growth factor in the augmentation of sodium channels in models of chronic pain

Nerve growth factor (NGF) was originally discovered as a neurotrophic factor essential for the survival of sensory and sympathetic neurons during development. However, in the adult NGF has been found to play an important role in nociceptor sensitization after tissue injury. The authors outline mechanisms by which NGF activation of its cognate receptor, tropomyosin-related kinase A receptor, regulates a host of ion channels, receptors, and signaling molecules to enhance acute and chronic pain. The authors also document that peripherally restricted antagonism of NGF-tropomyosin-related kinase A receptor signaling is effective for controlling human pain while appearing to maintain normal nociceptor function. Understanding whether there are any unexpected adverse events and how humans may change their behavior and use of the injured/degenerating tissue after significant pain relief without sedation will be required to fully appreciate the patient populations that may benefit from these therapies targeting NGF.

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Nerve growth factor-induced changes in sodium channels of rat PC12 pheochromocytoma cells

Neuroscience Research Supplements ◽

10.1016/0921-8696(87)90168-x ◽

1987 ◽

Vol 5 ◽

pp. S76

Author(s):

Kenshi Kamei ◽

Hiroshi Hatanaka ◽

Michihisa Miyake

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Sodium Channels ◽

Nerve Growth ◽

Pheochromocytoma Cells ◽

Pc12 Pheochromocytoma Cells ◽

Induced Changes

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A Virus-Like Particle-Based Anti-Nerve Growth Factor Vaccine Reduces Inflammatory Hyperalgesia: Potential Long-Term Therapy for Chronic Pain

The Journal of Immunology ◽

10.4049/jimmunol.1000030 ◽

2010 ◽

Vol 186 (3) ◽

pp. 1769-1780 ◽

Cited By ~ 20

Author(s):

Till A. Röhn ◽

William T. Ralvenius ◽

Jolly Paul ◽

Petra Borter ◽

Marcela Hernandez ◽

...

Keyword(s):

Chronic Pain ◽

Nerve Growth Factor ◽

Growth Factor ◽

Term Therapy ◽

Inflammatory Hyperalgesia ◽

Nerve Growth ◽

Virus Like Particle ◽

Long Term Therapy

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Nerve growth factor acts through cAMP-dependent protein kinase to increase the number of sodium channels in PC12 cells

Neuron ◽

10.1016/0896-6273(90)90048-k ◽

1990 ◽

Vol 4 (3) ◽

pp. 355-366 ◽

Cited By ~ 74

Author(s):

Daniel Kalman ◽

Bradley Wong ◽

Andrew E. Horvai ◽

Martin J. Cline ◽

Paul H. O'Lague

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Protein Kinase ◽

Pc12 Cells ◽

Sodium Channels ◽

Dependent Protein Kinase ◽

Nerve Growth ◽

Camp Dependent Protein Kinase ◽

Dependent Protein

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Anti-nerve growth factor monoclonal antibodies for the control of pain in dogs and cats

Veterinary Record ◽

10.1136/vr.104590 ◽

2018 ◽

Vol 184 (1) ◽

pp. 23-23 ◽

Cited By ~ 9

Author(s):

Masataka Enomoto ◽

Patrick W Mantyh ◽

Joanna Murrell ◽

John F Innes ◽

B Duncan X Lascelles

Keyword(s):

Chronic Pain ◽

Nerve Growth Factor ◽

Growth Factor ◽

Sympathetic Neurons ◽

Critical Role ◽

Current Status ◽

Effective Control ◽

Novel Therapy ◽

Nerve Growth ◽

Species Specific

Nerve growth factor (NGF) is essential for the survival of sensory and sympathetic neurons during development. However, in the adult, NGF and its interaction with tropomyosin receptor kinase A receptor (TrkA) has been found to play a critical role in nociception and nervous system plasticity in pain conditions. Thus, various monoclonal antibody (mAb) therapies targeting this pathway have been investigated in the development of new pharmacotherapies for chronic pain. Although none of the mAbs against NGF are yet approved for use in humans, they look very promising for the effective control of pain. Recently, species-specific anti-NGF mAbs for the management of osteoarthritis (OA)-associated pain in dogs and cats has been developed, and early clinical trials have been conducted. Anti-NGF therapy looks to be both very effective and very promising as a novel therapy against chronic pain in dogs and cats. This review outlines the mechanism of action of NGF, the role of NGF in osteoarthritis, research in rodent OA models and the current status of the development of anti-NGF mAbs in humans. Furthermore, we describe and discuss the recent development of species-specific anti-NGF mAbs for the treatment of OA-associated pain in veterinary medicine.

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Efficacy and Safety of an Anti-nerve Growth Factor Antibody (Frunevetmab) for the Treatment of Degenerative Joint Disease-Associated Chronic Pain in Cats: A Multisite Pilot Field Study

Frontiers in Veterinary Science ◽

10.3389/fvets.2021.610028 ◽

2021 ◽

Vol 8 ◽

Author(s):

Margaret E. Gruen ◽

Jamie A. E. Myers ◽

B. Duncan X. Lascelles

Keyword(s):

Chronic Pain ◽

Nerve Growth Factor ◽

Pain Management ◽

Growth Factor ◽

Unmet Need ◽

Degenerative Joint Disease ◽

Joint Disease ◽

Efficacy And Safety ◽

Nerve Growth ◽

Objectively Measured

Background: Pain management for cats with degenerative joint disease (DJD) remains a critical unmet need. Recent work has shown promise for a feline-specific anti-nerve growth factor monoclonal antibody (frunevetmab) to deliver safe and effective pain management. Our objectives were to evaluate the efficacy and safety of frunevetmab administered twice using two administration routes (subcutaneous and intravenous) compared to placebo.Methods: This was a randomized placebo-controlled, double-masked study. After a week-long pain and activity baseline, 126 cats were randomized to receive injections of frunevetmab (IV then SC; n = 42 or SC then SC; n = 43) or placebo (IV then SC; n = 41) on Days 0 and 28. Owners completed questionnaires on Days 14, 28, 42, and 56. Accelerometry data were collected continuously throughout.Results: Owner questionnaire results showed significant improvement in frunevetmab-treated cats [compared to placebo; (p < 0.05)] at Days 42 and 56; no difference was found between routes of administration for frunevetmab. All groups had decreased objectively measured weekly activity from baseline; frunevetmab-treated cats had a mean decrease of 0.9%, while placebo-treated cats had a mean decrease of 9.3%. Treatments were generally well-tolerated. The majority of adverse events included dermatitis/alopecia related to activity-monitor collars; these occurred in a higher percentage of frunevetmab, compared to placebo, treated cats.Conclusions and Clinical Relevance: Treatment with frunevetmab provided improvements in owner ratings of mobility over treatment with placebo; these results were supported by objectively measured accelerometry. Frunevetmab has the potential to address a critical gap in the treatment of chronic pain in cats.

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