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      NGF/TrkA Signaling as a Therapeutic Target for Pain

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      Pain Practice

      Wiley

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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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          Most cited references 52

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          Transduction of full-length TAT fusion proteins into mammalian cells: TAT-p27Kip1 induces cell migration.

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            Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis.

            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.
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              Pathophysiology of peripheral neuropathic pain: immune cells and molecules.

              Damage to the peripheral nervous system often leads to chronic neuropathic pain characterized by spontaneous pain and an exaggerated response to painful and/or innocuous stimuli. This pain condition is extremely debilitating and usually difficult to treat. Although inflammatory and neuropathic pain syndromes are often considered distinct entities, emerging evidence belies this strict dichotomy. Inflammation is a well-characterized phenomenon, which involves a cascade of different immune cell types, such as mast cells, neutrophils, macrophages, and T lymphocytes. In addition, these cells release numerous compounds that contribute to pain. Recent evidence suggests that immune cells play a role in neuropathic pain in the periphery. In this review we identify the different immune cell types that contribute to neuropathic pain in the periphery and release factors that are crucial in this particular condition.
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                Author and article information

                Journal
                Pain Practice
                Pain Pract
                Wiley
                15307085
                February 2016
                February 27 2016
                : 16
                : 2
                : 175-182
                Article
                10.1111/papr.12342
                26452158
                © 2016
                Product
                Self URI (article page): http://doi.wiley.com/10.1111/papr.12342

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