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      Role of Nerve Growth Factor in Orofacial Pain

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          Some chronic pain conditions in the orofacial region are common and the mechanisms underlying orofacial pain are unresolved. Nerve growth factor (NGF) is a member of a family of neurotrophins and regulates the growth, maintenance and development of neurons. Increasing evidence suggests that NGF plays a crucial role in the generation of pain and hyperalgesia in different pain states. This review investigates the role of NGF in orofacial pain and their underlying cellular mechanisms, which may provide essential guidance to drug-discovery programmes. A systemic literature search was conducted in Pubmed focusing on NGF and orofacial pain. Articles were reviewed, and those discussing in vitro studies, animal evidence, clinical course, and possible mechanisms were summarized. We found a hyperalgesic effect of NGF in peripheral sensitization in orofacial pain models. We also summarize the current knowledge regarding NGF-dependent pain mechanism, which is initiated by retrograde transport of the ligand-receptor complex, ensuing transcriptional regulation of many important nociceptor genes involved in nociceptive processing. Phase III trials suggest that anti-NGF drug is endorsed with anti-inflammatory and pain-relieving effects with good tolerance in a variety of pain conditions, including pain associated with osteoarthritis and chronic lower back pain. Based on the data reviewed herein, NGF is believed to be an important hyperalgesic mediator in orofacial pain. The identification of underlying mechanisms and pathways of orofacial pain opens new frontiers for pain management.

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          Most cited references 86

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          TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury.

          Cold hyperalgesia is a well-documented symptom of inflammatory and neuropathic pain; however, the underlying mechanisms of this enhanced sensitivity to cold are poorly understood. A subset of transient receptor potential (TRP) channels mediates thermosensation and is expressed in sensory tissues, such as nociceptors and skin. Here we report that the pharmacological blockade of TRPA1 in primary sensory neurons reversed cold hyperalgesia caused by inflammation and nerve injury. Inflammation and nerve injury increased TRPA1, but not TRPM8, expression in tyrosine kinase A-expressing dorsal root ganglion (DRG) neurons. Intrathecal administration of anti-nerve growth factor (anti-NGF), p38 MAPK inhibitor, or TRPA1 antisense oligodeoxynucleotide decreased the induction of TRPA1 and suppressed inflammation- and nerve injury-induced cold hyperalgesia. Conversely, intrathecal injection of NGF, but not glial cell line-derived neurotrophic factor, increased TRPA1 in DRG neurons through the p38 MAPK pathway. Together, these results demonstrate that an NGF-induced TRPA1 increase in sensory neurons via p38 activation is necessary for cold hyperalgesia. Thus, blocking TRPA1 in sensory neurons might provide a fruitful strategy for treating cold hyperalgesia caused by inflammation and nerve damage.
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            The role of N-methyl-D-aspartate (NMDA) receptors in pain: a review.

            There is accumulating evidence to implicate the importance of N-methyl-D-aspartate (NMDA) receptors to the induction and maintenance of central sensitization during pain states. However, NMDA receptors may also mediate peripheral sensitization and visceral pain. NMDA receptors are composed of NR1, NR2 (A, B, C, and D), and NR3 (A and B) subunits, which determine the functional properties of native NMDA receptors. Among NMDA receptor subtypes, the NR2B subunit-containing receptors appear particularly important for nociception, thus leading to the possibility that NR2B-selective antagonists may be useful in the treatment of chronic pain.
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              The neurotrophin family of neurotrophic factors: an overview.

              The neurotrophins are a family of closely related proteins that were first identified as survival factors for sympathetic and sensory neurons and have since been shown to control a number of aspects of survival, development, and function of neurons in both the central and peripheral nervous systems. Limiting quantities of neurotrophins during development control the numbers of surviving neurons to ensure a match between neurons and the requirement for a suitable density of target innervation. Biological effects of each of the four mammalian neurotrophins are mediated through activation of one or more of the three members of the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases (TrkA, TrkB, and TrkC). In addition, all neurotrophins activate the p75 neurotrophin receptor, a member of the tumor necrosis factor receptor superfamily. Neurotrophin engagement of Trk receptors leads to activation of Ras, phosphatidylinositol 3-kinase, phospholipase C-γ1, and signaling pathways controlled through these proteins, including the mitogen-activated protein kinases. Neurotrophin availability is required into adulthood, where they control synaptic function and plasticity and sustain neuronal cell survival, morphology, and differentiation. This chapter will provide an overview of neurotrophin biology, their receptors, and signaling pathways.

                Author and article information

                J Pain Res
                J Pain Res
                Journal of Pain Research
                24 July 2020
                : 13
                : 1875-1882
                [1 ]Department of Anesthesiology, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University , Guangzhou 510080, People’s Republic of China
                [2 ]Guangdong Provincial Key Laboratory of Stomatology , Guangzhou, 510080, People’s Republic of China
                [3 ]The Marine Biomedical Research Institute, Guangdong Medical University , Zhanjiang 524023, People’s Republic of China
                Author notes
                Correspondence: Wenguo Fan Department of Anesthesiology, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University , No. 74 Zhongshan Road 2, Guangzhou510080, People’s Republic of China Email fwg1207@tom.com
                © 2020 Mai et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 1, References: 94, Pages: 8
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 81771098 and 81541153
                This work was supported partly by the National Natural Science Foundation of China (No. 81771098 and 81541153).


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