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      NGF/TrkA Signaling as a Therapeutic Target for Pain.

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          Abstract

          Nerve growth factor (NGF) was first discovered approximately 60 years ago by Rita Levi-Montalcini as a protein that induces the growth of nerves. It is now known that NGF is also associated with Alzheimer's disease and intractable pain, and hence, it, along with its high-affinity receptor, tropomyosin receptor kinase (Trk) A, is considered to be 1 of the new targets for therapies being developed to treat these diseases. Anti-NGF antibody and TrkA inhibitors are known drugs that suppress NGF/TrkA signaling, and many drugs of these classes have been developed thus far. Interestingly, local anesthetics also possess TrkA inhibitory effects. This manuscript describes the development of an analgesic that suppresses NGF/TrkA signaling, which is anticipated to be 1 of the new methods to treat intractable pain.

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          Trk receptor tyrosine kinases: a bridge between cancer and neural development.

          Akira Nakagawara (2001)
          The proto-oncogene Trks encode the high-affinity receptor tyrosine kinases for neurotrophins of a nerve growth factor (NGF) family. The Trk signals spatiotemporally regulate neural development and maintenance of neural network. However, Trk was originally cloned as an oncogene fused with the tropomyosin gene in the extracellular domain. Accumulating evidence has demonstrated that the rearranged Trk oncogene is often observed in non-neuronal neoplasms such as colon and papillary thyroid cancers, while the signals through the receptors encoded by the proto-oncogene Trks regulate growth, differentiation and apoptosis of the tumors with neuronal origin such as neuroblastoma and medulloblastoma. The intracellular Trk signaling pathway is also different depending on the Trk family receptors, cell types and the grade of transformation. Furthermore, developmentally programmed cell death of neuron, which is largely regulated by neurotrophin signaling, is at least in part controlled by tumor suppressors p53 and p73 as well as their antagonist DeltaNp73. Thus, the Trks and their downstream signaling function in both ontogenesis and oncogenesis. In this short review, the dynamic role of the Trk family receptors signaling in neural development, neurogenic tumors and other cancers will be discussed.
          Article 0 comments Cited 125 times – based on 0 reviews     Review now
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            Transduction of full-length TAT fusion proteins into mammalian cells: TAT-p27Kip1 induces cell migration.

            H Nagahara, S Dowdy, N A Lissy … (1998)
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              Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis.

              Y Indo, M Tsuruta, Y Hayashida … (1996)
              Congenital insensitivity to pain with anhidrosis (CIPA; MIM 256800) is an autosomal-recessive disorder characterized by recurrent episodes of unexplained fever, anhidrosis (absence of sweating) and absence of reaction to noxious stimuli, self-mutilating behaviour and mental retardation. The genetic basis for CIPA is unknown. Nerve growth factor (NGF) induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons. Mice lacking the gene for TrkA, a receptor tyrosine kinase for NGF, share dramatic phenotypic features of CIPA, including loss of responses to painful stimuli, although anhidrosis is not apparent in these animals. We therefore considered the human TRKA homologue as a candidate for the CIPA gene. The mRNA and genomic DNA encoding TRKA were analysed in three unrelated CIPA patients who had consanguineous parents. We detected a deletion-, splice- and missense-mutation in the tyrosine kinase domain in these three patients. Our findings strongly suggest that defects in TRKA cause CIPA and that the NGF-TRKA system has a crucial role in the development and function of the nociceptive reception as well as establishment of thermoregulation via sweating in humans. These results also implicate genes encoding other TRK and neurotrophin family members as candidates for developmental defect(s) of the nervous system.
              Article 0 comments Cited 111 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (iso-abbrev): Pain Pract
                Title: Pain practice : the official journal of World Institute of Pain
                Publisher: Wiley
                ISSN (Electronic): 1533-2500
                ISSN (Print): 1530-7085
                Publication date (Electronic): Feb 2016
                Volume: 16
                Issue: 2
                Affiliations
                [1 ] Department of Anesthesiology and Pain Medicine, Hyogo College of Medicine, Hyogo, Japan.
                [2 ] Department of Pharmaceutical Health Care, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Hyogo, Japan.
                [3 ] Department of Anesthesiology and Reanimatology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
                Article
                DOI: 10.1111/papr.12342
                PubMed ID: 26452158
                SO-VID: a4965a40-4495-4cfe-af61-140148fbb7f0
                Copyright © © 2015 World Institute of Pain.
                History

                Keywords: NGF,TrkA,anti-NGF antibody,local anesthetic,nerve growth factor,pain,protein kinase,review,tanezumab,tropomyosin receptor kinase
                Data availability:
                Keywords: NGF, TrkA, anti-NGF antibody, local anesthetic, nerve growth factor, pain, protein kinase, review, tanezumab, tropomyosin receptor kinase

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