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Pain Sensitization
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
Nerve damage also results in an increased production of peptides, such as nerve growth factor (NGF), which normally regulate neuronal growth. NGF is a neurotropic peptide that activates the tyrosine kinase (Trk) receptor. Inflammation is associated with increased NGF expression and synthesis in peripheral tissues. NGF is important for the development of peripheral sensitization mediated by direct and indirect actions of inflammatory mediators on nociceptive afferents, mast cells and postganglionic efferents. Axonal transport of NGF has tropic effects within the spinal cord dorsal horn, resulting in central sensitization.
Neurotrophic Factors
Published in Martin Berry, Ann Logan, CNS Injuries: Cellular Responses and Pharmacological Strategies, 2019
The low-affinity p75 NGF receptor (p75NGFR)21–24 is a product of a different gene family and is a member of the tumor necrosis factor receptor superfamily. In contrast to the above-mentioned Trk receptor specificities, p75NGFR can bind all the neurotrophins. The p75NGFR provides ligand-binding specificity for NGF to TrkA, can enhance Trk phosphorylation in the presence of ligand, but can decrease TrkA autophosphorylation in the absence of NGF. In the peripheral nervous system p75NGFR facilitates retrograde transport of selected neurotrophins.26 The p75NGFR also has TrkA-independent signaling abilities through activation of sphingomyelin hydrolysis, which produces the lipid second messenger ceramide.27,28 Ceramide can induce apoptosis29,30 and recent in vitro and in vivo findings have revealed that p75NGFR can mediate neuronal apoptosis.31–33 Interestingly, activation of p75NGFR by all neurotrophins can produce ceramide, but in Schwann cells (which lack Trks), NGF, but not BDNF or NT-3, also causes activation of the transcription factor NFkB.34 This suggests that different ligands can activate different intracellular pathways through p75NGFR. The selective activation by different ligands of different signaling pathways that may result in cell death or survival through the same receptor may constitute a powerful therapeutic strategy.
Physiology of pain
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2015
Philip J. Siddal, Michael J. Cousins, Peter Kam
Nociceptors do not act simply as inert conductors of sensory information. Section of, or damage to, a peripheral nerve results in a number of biochemical, physiological and morphological changes. Damage to peripheral nerves will result in ectopic discharges near the site of damage and adjacent to the DRG (Figure 13.9). Nerve damage also results in an increased production of peptides, such as nerve growth factor (NGF), which normally regulate neuronal growth. NGF is a neurotropic peptide that activates the tyrosine kinase (Trk) receptor. Inflammation is associated with increased NGF expression and synthesis in peripheral tissues. NGF is important for the development of peripheral sensitization mediated by direct and indirect actions of inflammatory mediators on nociceptive afferents, mast cells and postganglionic efferents. Axonal transport of NGF has tropic effects within the spinal cord dorsal horn, resulting in central sensitization.
Ongoing and evolving clinical trials enhancing future colorectal cancer treatment strategies
Published in Expert Opinion on Investigational Drugs, 2022
Javier Ros, Nadia Saoudi, Francesc Salvà, Iosune Baraibar, Guzman Alonso, Josep Tabernero, Elena Elez
TRK receptor kinases are encoded by the neurotrophic tropomyosin receptor kinase genes NTRK, playing a crucial role in embryogenesis and in the regulation of different functions of the nervous system such as pain or memory [98]. Even though NTRK fusions were originally discovered in a CRC cell line, patients harboring NTRK fusions are a rare subgroup in mCRC (<0.5%) and have a poor prognosis [99–101]. They are more commonly detected in patients with mCRC and somatic hypermethylation of the MLH1 promoter (therefore dMMR and is not related to Lynch syndrome) and all RAS/BRAF wild-type tumors [102]. Nevertheless, the main relevance of this alteration lies in its feasible actionability. Both entrectinib and larotrectinib have demonstrated impressive efficacy in solid malignancies, although in gastrointestinal tumors the ORR was slightly lower [103–105]. Although the most prevalent mechanisms of resistance to larotrectinib are mutations that affect the affinity of larotrectinib for the kinase domain of the resulting fusion protein, recent data suggest that the parallel activation of MAPK signaling is a source of resistance to these treatments [106]. Although in November 2018 the FDA granted accelerated tissue-agnostic approval to larotrectinib for solid tumors with NTRK gene fusions, the identification of the subgroup of patients with mCRC who are candidates for testing for NTRK fusions remains elusive.
The Occurrence of Valvular Atrial Fibrillation: Involvement of NGF/TrKA Signaling Pathway
Published in Journal of Investigative Surgery, 2021
Qianli Wang, Yong Zhao, Xin Dong, Cong Li, Lin Zhou, Chengwei Zou, Xiaodong Li, Nannan Zhou, Junni Liu, Yuanyuan Sun, Jianchun Wang
TrkA is a specific trk receptor that binds to NGF and is crucial for maintaining sympathetic neuron health and stimulating axon regeneration. Previous studies have demonstrated that NGF/TrkA signaling play an important role in enhancing normal cardiac calcium cycling and normal cardiovascular system function [21,22]. After the association between NGF and the TrkA receptor was demonstrated, it was revealed that this triggers TrkA receptor autophosphorylation. Therefore, the protein level of TrkA phosphorylation of Trk was investigated in this study. The TrkA protein level was decreased in AF patients. The results from this study also indicated that activation of the downstream Akt pathway was inhibited, which was detected by the phosphorylation of its mediators Akt. In addition, proper TrkA transport and sorting mediates the function of NGF. However, the concentration of TrKA did not increase with the increasing of NGF. Previous studies illustrated that stimulated cells with NGF and measured TrkA at different times, TrKA concentration decreased with time due to TrkA degradation [23,24]. This may explain the decreasion of TrkA concentration. Thus, as NGF/TrkA signaling was necessary for the function of neurotrophins in both neurons and heart, it was speculated that neurotrophic signaling may be a key factor of the AF patients.
Transcriptomic and functional proteomics analyses to unveil the common and unique pathway(s) of neuritogenesis induced by Russell’s viper venom nerve growth factor in rat pheochromocytoma neuronal cells
Published in Expert Review of Proteomics, 2021
Taufikul Islam, Dev Madhubala, Rupak Mukhopadhyay, Ashis K. Mukherjee
Upon binding to the Trk receptor, NGF initiates a cascade of actions that are characterized by the activation of the cytosolic domain of the receptor [38]. The activation includes auto- and cross-phosphorylation of the cytosolic domain of the Trk receptor [39]. These autophosphorylation sites serve as docking sites for other specific pathway proteins such as PLCγ and Shc. Once activated, the sites serve as receptor-independent signaling pathway(s) [40]. The current study, using transcriptomic and functional proteomic analyses demonstrated the up-regulation and the down-regulation of neuritogenesis-specific pathways in RVV-NGFa-treated PC-12 cells, compared to control cells. The expressed pathways include the upregulation of Fas, p38 MAPK, VEGF, and FGF-mediated signaling pathways, and angiogenesis in the RVV-NGFa-treated PC-12 cells (Table 3a) that are commonly associated with neuritogenesis [41].