Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 -- 2723 2024-03-14 12:53:38 |
2 Reference format revised. Meta information modification 2723 2024-03-15 07:41:10 |

Video Upload Options

Do you have a full video?


Are you sure to Delete?
If you have any further questions, please contact Encyclopedia Editorial Office.
Xiong, H.; Hendrix, J.; Schabrun, S.; Wyns, A.; Campenhout, J.V.; Nijs, J.; Polli, A. Role of Brain-Derived Neurotrophic Factor in Chronic Pain. Encyclopedia. Available online: (accessed on 15 April 2024).
Xiong H, Hendrix J, Schabrun S, Wyns A, Campenhout JV, Nijs J, et al. Role of Brain-Derived Neurotrophic Factor in Chronic Pain. Encyclopedia. Available at: Accessed April 15, 2024.
Xiong, Huan-Yu, Jolien Hendrix, Siobhan Schabrun, Arne Wyns, Jente Van Campenhout, Jo Nijs, Andrea Polli. "Role of Brain-Derived Neurotrophic Factor in Chronic Pain" Encyclopedia, (accessed April 15, 2024).
Xiong, H., Hendrix, J., Schabrun, S., Wyns, A., Campenhout, J.V., Nijs, J., & Polli, A. (2024, March 14). Role of Brain-Derived Neurotrophic Factor in Chronic Pain. In Encyclopedia.
Xiong, Huan-Yu, et al. "Role of Brain-Derived Neurotrophic Factor in Chronic Pain." Encyclopedia. Web. 14 March, 2024.
Role of Brain-Derived Neurotrophic Factor in Chronic Pain

Chronic pain is sustained, in part, through the intricate process of central sensitization (CS), marked by maladaptive neuroplasticity and neuronal hyperexcitability within central pain pathways. Accumulating evidence suggests that CS is also driven by neuroinflammation in the peripheral and central nervous system. In any chronic disease, the search for perpetuating factors is crucial in identifying therapeutic targets and developing primary preventive strategies. The brain-derived neurotrophic factor (BDNF) emerges as a critical regulator of synaptic plasticity, serving as both a neurotransmitter and neuromodulator. Mounting evidence supports BDNF’s pro-nociceptive role, spanning from its pain-sensitizing capacity across multiple levels of nociceptive pathways to its intricate involvement in CS and neuroinflammation.

chronic pain BDNF brain-derived neurotrophic factor

1. Introduction

Chronic pain represents a pervasive global health challenge, causing significant disability and socioeconomic burdens [1][2]. With over 30% of the world’s population grappling with chronic pain, it has emerged as a formidable public health concern, posing substantial challenges for both researchers and clinicians [3][4]. Compounding the issue is the inadequacy of existing drug treatments, which often fall short in terms of efficacy and tolerability, leaving more than half of patients with chronic pain without sufficient relief [5][6][7][8]. Groundbreaking research in neuroscience has led the World Health Organization to recognize chronic pain as a disease characterized by intricate functional and structural changes in the brain, neuroinflammation, and increased sensitivity of the central nervous system (CNS) to nociceptive input—central sensitization (CS) [9][10][11][12][13]. In essence, chronic pain not only represents prolonged acute pain but also involves maladaptive neuroplastic changes and sensitization of the nociceptive pathways in the nervous system, extending beyond a simple pain–damage association [14].
In recent years, intensive research has focused on understanding the biochemical and molecular alterations contributing to chronic pain. One promising avenue of exploration centers around the brain-derived neurotrophic factor (BDNF) gene, which influences circulating levels of BDNF, and has been implicated in initiating and/or perpetuating neuronal hyperexcitability, maladaptive neuroplasticity, and disinhibition at different levels of nociceptive pathways [15]. BDNF assumes a central role in promoting brain homeostasis and neuronal survival, and also serves as a critical regulator of synaptic plasticity [16]. Despite its crucial role in maintaining normal physiological functions, a less positive perspective emerges concerning chronic pain, where mounting evidence suggests a pro-nociceptive role for BDNF [17][18]. Consequently, BDNF is increasingly acknowledged as a pivotal perpetuating factor in chronic pain.

2. The Physiological Role of BDNF

Since its discovery, BDNF has garnered extensive attention as one of the most extensively studied neurotrophins, owing to its multipotent impacts on various physiological and pathological functions within the nervous system. Recognized for its robust protective actions promoting brain homeostasis, neuronal survival, synaptogenesis, plasticity, and cognitive function [16][19][20][21], BDNF exhibits activity throughout all stages of development and aging [22][23]. BDNF plays a crucial role in initiating compensatory processes that facilitate recovery and/or alleviate chronic adverse effects caused by injury or disease in the nervous system [19].
Like other neurotrophins, BDNF is initially synthesized as a pre-pro-protein. The pre-protein undergoes rapid cleavage to form pro-BDNF, which then assembles in homodimers [24]. The pro-BDNF can be subsequently cleaved by extracellular proteases at synapses and converted to mature BDNF [25]. BDNF exerts its biological functions via two distinct classes of receptors: the high-affinity tropomyosin receptor kinase B (TrkB) and the low-affinity p75 neurotrophin receptor (p75NTR). Pro-BDNF exhibits a preference for binding to p75NTR, while mature BDNF preferentially binds the TrkB receptor. In general, binding to TrkB receptors allows BDNF to modulate and promote neuronal survival, neuroprotection, and long-term potentiation (LTP)—a form of long-term synaptic plasticity in nociceptive pathways [26]. Conversely, binding to p75NTR receptors may regulate neuronal apoptosis, axonal process pruning, and long-term depression (LTD) [27][28]. The contrasting effects of BDNF/TrkB and BDNF/p75NTR signaling form a delicate “yin-yang” system that finely manipulates neuroplasticity and neuronal excitability [29].
The functionality of the central nervous system (CNS) is intricately tied to available BDNF expression. Predominantly synthesized and expressed in various neuronal cells of the brain, such as sensory neurons and motor neurons [30][31][32], BDNF is also produced, to a lesser extent, in non-neuronal cells such as glial cells and immune cells [33][34]. Available BDNF was found in different regions of the brain, including the neocortex, pyriform cortex, amygdala, hippocampus, claustrum, thalamus, striatum, hypothalamus, and brainstem [30][35]. In addition, circulating BDNF derives from both peripheral and cerebral sources [36][37][38]

3. The Role of BDNF in Patients with Chronic Pain

3.1. The Role of BDNF in Central Sensitization

Chronic pain is known to be associated with CS, a process by which the nociceptive signals of neurons at every level of nociceptive pathways are gradually enhanced [39]. CS is responsible for both hyperalgesia and allodynia. At the cellular level, CS occurs in part as a result of enhanced and more efficient synaptic communication between neurons, which primarily involves the reshaping of neuronal circuits, neuronal hyperexcitability, and a reduction in synaptic inhibition [40][41].
Given its essential role throughout the nervous system, BDNF has been implicated in the induction and maintenance of the CS. For example, the activation of BDNF/TrkB signaling has been linked to increased pain signaling mechanisms [42]. BDNF, upon release from the dorsal root ganglia, engages with TrkB receptors located on primary afferent nerve endings and post-synaptic tracts in the spinal cord. This interaction serves to amplify and potentiate ascending sensory signals, contributing to the perpetuation of CS. As expected, pain signaling mechanisms can be reversed through intrathecal administration of TrkB inhibitors, which attenuates nociceptive response [43][44]. It is crucial to recognize that CS involves an activity-dependent increase in the excitability of dorsal horn neurons [40], and BDNF contributes to this process by promoting a gradual increase in neuronal excitability and synaptic plasticity in the spinal dorsal horn [45][46][47]
Persistent CS has been described as a maladaptive neuroplasticity process in chronic pain [48][49]. BDNF can regulate synaptic plasticity in an activity-dependent manner, contributing to LTP [50][51]. LTP involves neuronal adaptation at the presynaptic (e.g., increased ability to produce neurotransmitters) and postsynaptic (e.g., increased ability to bind neurotransmitters to receptors) levels, resulting in enhanced synaptic efficiency and, consequently, an increase in the excitability of neuronal pathways [52][53][54]. The synapses are a critical link in inter-neuronal connections, and an increase in their number can facilitate the transmission of nociceptive signals between neurons, potentially contributing to CS [55]. However, BDNF knockout specimens exhibited a decrease in preganglionic synaptic innervation density to sympathetic neurons, suggesting that BDNF has the ability to increase synaptic density [22].
Finally, dysfunction in the descending inhibitory nociceptive modulation pathways emerges as a crucial contributor to CS. Recent studies have unveiled reduced intracortical inhibition in different pain populations compared to healthy subjects, with this reduction being associated with more severe pain symptoms [56][57][58][59]. Disinhibition of GABAergic and glycinergic synaptic transmission in nociceptive circuitry is crucial to the generation of chronic pain. Centrally, BDNF can weaken GABAergic inhibitory synapses by reducing the expression of potassium-chloride cotransporter 2 (KCC2), thus suppressing the intrinsic inhibitory circuits [46][60][61]

3.2. Neuroinflammation Drives Chronic Pain via Glial-Derived BDNF and CS

While acute inflammation is responsible for triggering acute pain sensations, neuroinflammation is supposed to play an important role in the chronification and persistence of pain [62][63]. This neuroinflammation is initiated by the activity-dependent release of glial activators, including neurotransmitters, chemokines, and proteases. This release stems from the central terminals of primary afferent neurons or is prompted by the disruption of the blood–brain barrier. Neuroinflammation is characterized by the activation of glial cells such as microglia and astrocytes, the infiltration of immune cells, vasculature changes, and an increased release of inflammatory and glial mediators like cytokines, chemokines, and BDNF [64]. These glial mediators can significantly regulate both excitatory and inhibitory synaptic transmission, thereby contributing to CS and enhanced chronic pain states.
In the spinal cord and brain, glial cells also produce nerve growth factors and neurotrophins, such as BDNF and basic fibroblast growth factor (bFGF), which can affect neuronal function and may contribute to neurotoxicity in several brain pathologies [19]. In fact, the expression of neurotrophins is often upregulated in chronic inflammatory diseases due to their involvement in energy homeostasis [65]. For example, microglial activation following peripheral nerve injury upregulates purinergic receptors, especially P2 × 4R, leading to p38-MAPK phosphorylation and subsequent BDNF release [66]. This microglial-derived BDNF has been implicated in facilitating neuropathic pain and morphine hyperalgesia [67][68]
A key player in inflammatory activation is the nuclear factor-kappa B (NF-κB), a transcription factor that triggers the expression of pro- and anti-apoptotic genes [69]. Remarkably, the binding of BDNF to the TrkB receptor serves as a trigger for the induction of the NF-κB expression. Furthermore, chronic inflammatory pain has been reported to induce an upregulation of TrkB mRNA and protein expression in the dorsal horn [70]. An additional layer of complexity arises from a p75NTR-mediated effect on NF-κB expression, as evidence suggests that peripheral inflammation induces an upregulation of pro-BDNF and p75NTR in the spinal cord [71][72]. With the activation of p75NTR, pro-BDNF can activate several downstream signaling pathways, including extracellular signal-regulated kinase (ERK)1 and ERK2, NF-κB, and c-Jun N-terminal kinase (JNK) pathways, further promoting the neuroinflammatory state [73][74][75]. These signaling pathways can trigger a series of changes, including neuronal hyperexcitability, LTP, maladaptive neuroplasticity, and an imbalance in excitatory/inhibitory neurotransmission—all of which are intricately involved in the process of CS (Figure 1). This cycle persists as long as the stressor exists, potentially evolving into a serious chronic pain state. Hence, neuroinflammation may drive chronic pain via CS, which can be induced and maintained by cytokines, chemokines, BDNF, and other glia-produced mediators.
Figure 1. The role of BDNF in central sensitization and neuroinflammation.

3.3. Pro-Nociceptive and Anti-Nociceptive Role of BDNF

Emerging evidence from human studies has revealed higher cerebrospinal fluid [76], plasma [77][78][79], and serum [80][81][82][83] levels of BDNF in patients with chronic pain compared to healthy individuals, which were positively correlated with more severe pain symptoms. For instance, higher serum BDNF levels were associated with lower pressure pain thresholds in patients with fibromyalgia [83]. Notably, a one-month treatment with duloxetine (an antidepressant) not only alleviated pain but also led to reduced serum BDNF levels [84], supporting a pro-nociceptive role of BDNF in chronic pain. Recent evidence also supports the pro-nociceptive role of BDNF in arthritis pain [85], with higher plasma BDNF levels observed in patients with knee osteoarthritis compared to healthy controls, positively correlating with self-reported pain levels [79]. BDNF and TrkB were identified in nerve fascicles within synovial tissue from both patients with osteoarthritis and animal models of inflammatory arthritis [86][87]. As expected, experimental injection of peripheral BDNF increased pain behavior [87].
Despite previous studies indicating a strong involvement of BDNF in the nociceptive system, its precise role remains uncertain. This uncertainty is further compounded by conflicting findings, with some research indicating a potential anti-inflammatory effect [88][89][90]. For instance, preliminary evidence from animal research suggests that the release of BDNF can alleviate allodynia and hyperalgesia induced by chronic constriction injury [91]. Additionally, BDNF shows anti-inflammatory effects on the animal brain [92], and experimentally induced inflammation, such as the infusion of IL-1 into the hippocampus, and diminishes BDNF transcription capacity [93]. Several explanations may account for its potential analgesic effect. Firstly, BDNF is involved in the regulation of neural circuits, and alterations in neural circuitry may affect inflammatory responses. Emerging evidence suggests that BDNF can inhibit neuroinflammation and regulate cognitive functions [94]

3.4. Genetics and BDNF in Chronic Pain

Over the past decade, the identification of altered BDNF levels in individuals with chronic pain has guided many genetic studies, revealing these alterations to be largely genetically determined. Specifically, mutations in the BDNF gene have been found to downregulate its secretion and expression, thereby diminishing its impact on the nervous system [95]. The single-nucleotide polymorphism rs6265 in the BDNF gene, located in the 5′-prodomain of immature BDNF protein and often referred to as Val66Met [95][96], has emerged as a key player in shaping pain perception and pain-related symptoms [97][98], and is associated with vulnerability to different chronic pain disorders [99][100][101]. The Val/Val genotype has been linked to a distinct propensity for fibromyalgia symptoms and increased pain catastrophizing [100].
BDNF, with its influence on crucial neuronal processes, is subject to complex changes in function due to its polymorphism, particularly in modulating neuroplasticity [51]. Evidence suggests that BDNF polymorphisms can serve as predictors for responses to experimental pain stimulation and non-invasive brain stimulation techniques, contributing to large interindividual variability in stimulation effects [102][103]

3.5. The Epigenetic Regulation of BDNF Expression in Chronic Pain

Chronic pain intricately involves abnormal gene expression within the neural cells responsible for processing nociceptive signals in the brain [104][105]. While genetic alterations offer a partial explanation for chronic pain, the emerging field of epigenetics provides a more nuanced and dynamic perspective by unraveling the gene expression patterns associated with chronic pain [106][107]. Recent studies revealed that epigenetic mechanisms, including histone acetylation [108], non-coding RNAs [108][109], and DNA methylation [110][111][112], can influence the expression of BDNF (Figure 2). These epigenetic modifications may contribute to the pathogenesis and symptomatology of chronic pain.
Figure 2. The epigenetic regulation of BDNF expression.

4. Clinical and Methodological Implications

4.1. BDNF Treatment for Chronic Pain in a Broader Picture

BDNF serves as a driving force behind neuroplasticity in the context of chronic pain, positioning it as a potential biomarker and a novel therapeutic target. Although our understanding of BDNF’s role in pain processing remains limited, emerging evidence suggests its pro-nociceptive involvement in initiating and sustaining CS among individuals with persistent pain. Consequently, exploring the pharmacological and non-pharmacological manipulation of BDNF opens up crucial avenues for research. Various therapeutic strategies known to influence the release of BDNF have been extensively studied for regulating BDNF levels in patients with chronic pain, including neuromodulation techniques, BDNF-blocking therapies, and exercise therapy.
Neuromodulation techniques, such as transcranial direct current stimulation (tDCS), emerge as a promising treatment with analgesic properties [113][114][115]. By interfering with ongoing neural activity associated with pain processing and manipulating neuroplasticity and cortical excitability in specific brain regions, tDCS has been reported to improve pain and pain-related symptoms in patients with chronic pain [116][117]. While the exact mechanisms underlying these effects remain unclear, accumulating research suggests that the impact of tDCS may be neuroplasticity-state-dependent [118][119], with alterations in BDNF levels predicting the effects of tDCS on behavioral outcomes [120][121]. In other words, the analgesic effect of tDCS may depend on changes in endogenous BDNF levels [122][123], as BDNF is a driving force behind neuroplasticity [49].
Exercise therapy seems to hold the capability to influence BDNF expression. Recent insights from a systematic review and meta-analysis within pain populations reveal an upregulation of BDNF expression in peripheral blood following diverse physical activities, accompanied by decreasing pain severity [124][125][126]. Similarly promising outcomes have been observed in healthy individuals [127]. However, the duration of exercise can yield varied results, with a single session or acute exercise reportedly increasing BDNF levels, while long-term or regular exercise may reduce them [128][129][130]

4.2. Using BDNF as an Objective Biomarker

Peripheral blood BDNF has been proposed as a potential biomarker related to disease activity and neuroprogression in various diseases [131][132][133], speculated to mirror alterations in brain expression of BDNF. This intricate relationship between brain and blood BDNF levels underscores the potential utility of peripheral measurements as informative markers for CNS dynamics. Given the challenges in directly measuring BDNF levels in the human brain, most clinical studies resort to using plasma or serum samples as proxies [134][135].
BDNF polymorphisms have emerged as promising pain biomarkers. Specifically, the BDNF Val66Met polymorphism has been detected in diverse chronic pain populations, providing valuable insights into the susceptibility to distinct chronic pain conditions and the considerable interindividual variations in responses to various pain therapies [100][136][137]. Importantly, current literature suggests that BDNF polymorphisms can be reliably measured in both peripheral blood and buccal swab samples, making them accessible for potential diagnostic applications. Moreover, the development of tests to detect and define chronic pain conditions in the presence of the Val66Met polymorphism is an intriguing prospect. Several techniques, such as genotyping assays or real-time polymerase chain reaction (PCR) methods, could be explored to identify this specific genetic variant in blood samples.
The absence of biomarkers for diagnosing chronic pain remains a significant challenge in clinical practice. Typically, pain severity is assessed through the patient’s subjective report, an approach constrained by difficulties in quantification, reliability, and interparticipant comparability. The integration of objective biomarkers directly linked to the presence and severity of chronic pain would significantly (a) enhance the diagnosis and classification of pain pathophysiology, (b) assist with disease prognostication or predicting therapy responses, and (c) facilitate the development of innovative, mechanism-based treatment approaches, thereby reducing the reliance on long-term opioid use. Overall, BDNF is one of the most promising biomarkers for chronic pain disorders; however, a definitive clinical validation is still lacking.


  1. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018, 392, 1789–1858.
  2. GBD 2021 Low Back Pain Collaborators. Global, regional, and national burden of low back pain, 1990–2020, its attributable risk factors, and projections to 2050: A systematic analysis of the Global Burden of Disease Study 2021. Lancet Rheumatol. 2023, 5, e316–e329.
  3. Cohen, S.P.; Vase, L.; Hooten, W.M. Chronic pain: An update on burden, best practices, and new advances. Lancet 2021, 397, 2082–2097.
  4. Mills, S.E.E.; Nicolson, K.P.; Smith, B.H. Chronic pain: A review of its epidemiology and associated factors in population-based studies. Br. J. Anaesth. 2019, 123, e273–e283.
  5. Bannister, K.; Sachau, J.; Baron, R.; Dickenson, A.H. Neuropathic Pain: Mechanism-Based Therapeutics. Annu. Rev. Pharmacol. Toxicol. 2020, 60, 257–274.
  6. Taneja, A.; Della Pasqua, O.; Danhof, M. Challenges in translational drug research in neuropathic and inflammatory pain: The prerequisites for a new paradigm. Eur. J. Clin. Pharmacol. 2017, 73, 1219–1236.
  7. Maher, D.P.; Wong, C.H.; Siah, K.W.; Lo, A.W. Estimates of Probabilities of Successful Development of Pain Medications: An Analysis of Pharmaceutical Clinical Development Programs from 2000 to 2020. Anesthesiology 2022, 137, 243–251.
  8. Basbaum, A.I.; Braz, J.M. Cell transplants to treat the “disease” of neuropathic pain and itch. Pain 2016, 157 (Suppl. 1), S42–S47.
  9. Moayedi, M.; Weissman-Fogel, I.; Salomons, T.V.; Crawley, A.P.; Goldberg, M.B.; Freeman, B.V.; Tenenbaum, H.C.; Davis, K.D. Abnormal gray matter aging in chronic pain patients. Brain Res. 2012, 1456, 82–93.
  10. Nijs, J.; George, S.Z.; Clauw, D.J.; Fernández-de-las-Peñas, C.; Kosek, E.; Ickmans, K.; Fernández-Carnero, J.; Polli, A.; Kapreli, E.; Huysmans, E.; et al. Central sensitisation in chronic pain conditions: Latest discoveries and their potential for precision medicine. Lancet Rheumatol. 2021, 3, e383–e392.
  11. Kregel, J.; Meeus, M.; Malfliet, A.; Dolphens, M.; Danneels, L.; Nijs, J.; Cagnie, B. Structural and functional brain abnormalities in chronic low back pain: A systematic review. Semin. Arthritis Rheum. 2015, 45, 229–237.
  12. Albrecht, D.S.; Forsberg, A.; Sandstrom, A.; Bergan, C.; Kadetoff, D.; Protsenko, E.; Lampa, J.; Lee, Y.C.; Hoglund, C.O.; Catana, C.; et al. Brain glial activation in fibromyalgia—A multi-site positron emission tomography investigation. Brain Behav. Immun. 2019, 75, 72–83.
  13. Arendt-Nielsen, L.; Morlion, B.; Perrot, S.; Dahan, A.; Dickenson, A.; Kress, H.G.; Wells, C.; Bouhassira, D.; Mohr Drewes, A. Assessment and manifestation of central sensitisation across different chronic pain conditions. Eur. J. Pain 2018, 22, 216–241.
  14. Kuner, R.; Flor, H. Structural plasticity and reorganisation in chronic pain. Nat. Rev. Neurosci. 2016, 18, 20–30.
  15. Smith, P.A. BDNF: No gain without pain? Neuroscience 2014, 283, 107–123.
  16. Kowianski, P.; Lietzau, G.; Czuba, E.; Waskow, M.; Steliga, A.; Morys, J. BDNF: A Key Factor with Multipotent Impact on Brain Signaling and Synaptic Plasticity. Cell Mol. Neurobiol. 2018, 38, 579–593.
  17. Dussan-Sarria, J.A.; da Silva, N.R.J.; Deitos, A.; Stefani, L.C.; Laste, G.; Souza, A.; Torres, I.L.S.; Fregni, F.; Caumo, W. Higher Cortical Facilitation and Serum BDNF Are Associated with Increased Sensitivity to Heat Pain and Reduced Endogenous Pain Inhibition in Healthy Males. Pain Med. 2018, 19, 1578–1586.
  18. Wei, X.; Wang, L.; Hua, J.; Jin, X.H.; Ji, F.; Peng, K.; Zhou, B.; Yang, J.; Meng, X.W. Inhibiting BDNF/TrkB.T1 receptor improves resiniferatoxin-induced postherpetic neuralgia through decreasing ASIC3 signaling in dorsal root ganglia. J. Neuroinflamm. 2021, 18, 96.
  19. Lima Giacobbo, B.; Doorduin, J.; Klein, H.C.; Dierckx, R.; Bromberg, E.; de Vries, E.F.J. Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation. Mol. Neurobiol. 2019, 56, 3295–3312.
  20. Notaras, M.; van den Buuse, M. Neurobiology of BDNF in fear memory, sensitivity to stress, and stress-related disorders. Mol. Psychiatry 2020, 25, 2251–2274.
  21. Teixeira, A.L.; Barbosa, I.G.; Diniz, B.S.; Kummer, A. Circulating levels of brain-derived neurotrophic factor: Correlation with mood, cognition and motor function. Biomark. Med. 2010, 4, 871–887.
  22. Park, H.; Poo, M.M. Neurotrophin regulation of neural circuit development and function. Nat. Rev. Neurosci. 2013, 14, 7–23.
  23. Mattson, M.P.; Maudsley, S.; Martin, B. BDNF and 5-HT: A dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci. 2004, 27, 589–594.
  24. Hempstead, B.L. Brain-Derived Neurotrophic Factor: Three Ligands, Many Actions. Trans. Am. Clin. Climatol. Assoc. 2015, 126, 9–19.
  25. Zhang, J.C.; Yao, W.; Hashimoto, K. Brain-derived Neurotrophic Factor (BDNF)-TrkB Signaling in Inflammation-related Depression and Potential Therapeutic Targets. Curr. Neuropharmacol. 2016, 14, 721–731.
  26. Andero, R.; Choi, D.C.; Ressler, K.J. BDNF-TrkB receptor regulation of distributed adult neural plasticity, memory formation, and psychiatric disorders. Prog. Mol. Biol. Transl. Sci. 2014, 122, 169–192.
  27. Cui, Y.H.; Zhou, S.F.; Liu, Y.; Wang, S.; Li, F.; Dai, R.P.; Hu, Z.L.; Li, C.Q. Injection of Anti-proBDNF Attenuates Hippocampal-Dependent Learning and Memory Dysfunction in Mice With Sepsis-Associated Encephalopathy. Front. Neurosci. 2021, 15, 665757.
  28. Woo, N.H.; Teng, H.K.; Siao, C.J.; Chiaruttini, C.; Pang, P.T.; Milner, T.A.; Hempstead, B.L.; Lu, B. Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat. Neurosci. 2005, 8, 1069–1077.
  29. Lu, B.; Pang, P.T.; Woo, N.H. The yin and yang of neurotrophin action. Nat. Rev. Neurosci. 2005, 6, 603–614.
  30. Hofer, M.; Pagliusi, S.R.; Hohn, A.; Leibrock, J.; Barde, Y.A. Regional distribution of brain-derived neurotrophic factor mRNA in the adult mouse brain. EMBO J. 1990, 9, 2459–2464.
  31. Brady, R.; Zaidi, S.I.; Mayer, C.; Katz, D.M. BDNF is a target-derived survival factor for arterial baroreceptor and chemoafferent primary sensory neurons. J. Neurosci. 1999, 19, 2131–2142.
  32. Biane, J.; Conner, J.M.; Tuszynski, M.H. Nerve growth factor is primarily produced by GABAergic neurons of the adult rat cortex. Front. Cell Neurosci. 2014, 8, 220.
  33. Bejot, Y.; Prigent-Tessier, A.; Cachia, C.; Giroud, M.; Mossiat, C.; Bertrand, N.; Garnier, P.; Marie, C. Time-dependent contribution of non neuronal cells to BDNF production after ischemic stroke in rats. Neurochem. Int. 2011, 58, 102–111.
  34. Taves, S.; Berta, T.; Chen, G.; Ji, R.R. Microglia and spinal cord synaptic plasticity in persistent pain. Neural Plast. 2013, 2013, 753656.
  35. Yan, Q.; Rosenfeld, R.D.; Matheson, C.R.; Hawkins, N.; Lopez, O.T.; Bennett, L.; Welcher, A.A. Expression of brain-derived neurotrophic factor protein in the adult rat central nervous system. Neuroscience 1997, 78, 431–448.
  36. Nakahashi, T.; Fujimura, H.; Altar, C.A.; Li, J.; Kambayashi, J.; Tandon, N.N.; Sun, B. Vascular endothelial cells synthesize and secrete brain-derived neurotrophic factor. FEBS Lett. 2000, 470, 113–117.
  37. Tamura, S.; Suzuki, H.; Hirowatari, Y.; Hatase, M.; Nagasawa, A.; Matsuno, K.; Kobayashi, S.; Moriyama, T. Release reaction of brain-derived neurotrophic factor (BDNF) through PAR1 activation and its two distinct pools in human platelets. Thromb. Res. 2011, 128, e55–e61.
  38. Le Blanc, J.; Fleury, S.; Boukhatem, I.; Belanger, J.C.; Welman, M.; Lordkipanidze, M. Platelets Selectively Regulate the Release of BDNF, But Not That of Its Precursor Protein, proBDNF. Front. Immunol. 2020, 11, 575607.
  39. Meacham, K.; Shepherd, A.; Mohapatra, D.P.; Haroutounian, S. Neuropathic Pain: Central vs. Peripheral Mechanisms. Curr. Pain. Headache Rep. 2017, 21, 28.
  40. Latremoliere, A.; Woolf, C.J. Central sensitization: A generator of pain hypersensitivity by central neural plasticity. J. Pain 2009, 10, 895–926.
  41. Retamal, J.; Reyes, A.; Ramirez, P.; Bravo, D.; Hernandez, A.; Pelissier, T.; Villanueva, L.; Constandil, L. Burst-Like Subcutaneous Electrical Stimulation Induces BDNF-Mediated, Cyclotraxin B-Sensitive Central Sensitization in Rat Spinal Cord. Front. Pharmacol. 2018, 9, 1143.
  42. Wang, H.; Wei, Y.; Pu, Y.; Jiang, D.; Jiang, X.; Zhang, Y.; Tao, J. Brain-derived neurotrophic factor stimulation of T-type Ca(2+) channels in sensory neurons contributes to increased peripheral pain sensitivity. Sci. Signal 2019, 12, eaaw2300.
  43. Echeverry, S.; Shi, X.Q.; Yang, M.; Huang, H.; Wu, Y.; Lorenzo, L.E.; Perez-Sanchez, J.; Bonin, R.P.; De Koninck, Y.; Zhang, J. Spinal microglia are required for long-term maintenance of neuropathic pain. Pain 2017, 158, 1792–1801.
  44. Ramer, L.M.; McPhail, L.T.; Borisoff, J.F.; Soril, L.J.; Kaan, T.K.; Lee, J.H.; Saunders, J.W.; Hwi, L.P.; Ramer, M.S. Endogenous TrkB ligands suppress functional mechanosensory plasticity in the deafferented spinal cord. J. Neurosci. 2007, 27, 5812–5822.
  45. Sikandar, S.; Minett, M.S.; Millet, Q.; Santana-Varela, S.; Lau, J.; Wood, J.N.; Zhao, J. Brain-derived neurotrophic factor derived from sensory neurons plays a critical role in chronic pain. Brain 2018, 141, 1028–1039.
  46. Zhang, Z.; Wang, X.; Wang, W.; Lu, Y.G.; Pan, Z.Z. Brain-derived neurotrophic factor-mediated downregulation of brainstem K+-Cl- cotransporter and cell-type-specific GABA impairment for activation of descending pain facilitation. Mol. Pharmacol. 2013, 84, 511–520.
  47. Lu, V.B.; Ballanyi, K.; Colmers, W.F.; Smith, P.A. Neuron type-specific effects of brain-derived neurotrophic factor in rat superficial dorsal horn and their relevance to ‘central sensitization’. J. Physiol. 2007, 584, 543–563.
  48. Woolf, C.J. Central sensitization: Implications for the diagnosis and treatment of pain. Pain 2011, 152, S2–S15.
  49. Nijs, J.; Meeus, M.; Versijpt, J.; Moens, M.; Bos, I.; Knaepen, K.; Meeusen, R. Brain-derived neurotrophic factor as a driving force behind neuroplasticity in neuropathic and central sensitization pain: A new therapeutic target? Expert. Opin. Ther. Targets 2015, 19, 565–576.
  50. Wang, C.S.; Kavalali, E.T.; Monteggia, L.M. BDNF signaling in context: From synaptic regulation to psychiatric disorders. Cell 2022, 185, 62–76.
  51. Cappoli, N.; Tabolacci, E.; Aceto, P.; Dello Russo, C. The emerging role of the BDNF-TrkB signaling pathway in the modulation of pain perception. J. Neuroimmunol. 2020, 349, 577406.
  52. Zhuo, M. A synaptic model for pain: Long-term potentiation in the anterior cingulate cortex. Mol. Cells 2007, 23, 259–271.
  53. Cheng, Q.; Song, S.H.; Augustine, G.J. Calcium-Dependent and Synapsin-Dependent Pathways for the Presynaptic Actions of BDNF. Front. Cell Neurosci. 2017, 11, 75.
  54. Metsis, M.; Timmusk, T.; Arenas, E.; Persson, H. Differential usage of multiple brain-derived neurotrophic factor promoters in the rat brain following neuronal activation. Proc. Natl. Acad. Sci. USA 1993, 90, 8802–8806.
  55. Zheng, Y.; Zhou, Y.; Wu, Q.; Yue, J.; Ying, X.; Li, S.; Lou, X.; Yang, G.; Tu, W.; Zhou, K.; et al. Effect of electroacupuncture on the expression of P2 x 4, GABAA gamma 2 and long-term potentiation in spinal cord of rats with neuropathic pain. Brain Res. Bull. 2020, 162, 1–10.
  56. Hollins, M.; Bryen, C.P.; Taylor, D. Effects of chronic pain history on perceptual and cognitive inhibition. Exp. Brain Res. 2020, 238, 321–332.
  57. Caumo, W.; Deitos, A.; Carvalho, S.; Leite, J.; Carvalho, F.; Dussan-Sarria, J.A.; Lopes Tarrago Mda, G.; Souza, A.; Torres, I.L.; Fregni, F. Motor Cortex Excitability and BDNF Levels in Chronic Musculoskeletal Pain According to Structural Pathology. Front. Hum. Neurosci. 2016, 10, 357.
  58. Simis, M.; Imamura, M.; de Melo, P.S.; Marduy, A.; Pacheco-Barrios, K.; Teixeira, P.E.P.; Battistella, L.; Fregni, F. Increased motor cortex inhibition as a marker of compensation to chronic pain in knee osteoarthritis. Sci. Rep. 2021, 11, 24011.
  59. Soldatelli, M.D.; Siepmann, T.; Illigens, B.M.; Souza Dos Santos, V.; Lucena da, S.T.I.; Fregni, F.; Caumo, W. Mapping of predictors of the disengagement of the descending inhibitory pain modulation system in fibromyalgia: An exploratory study. Br. J. Pain 2021, 15, 221–233.
  60. Zhao, S.; Wang, F.; Wang, L.; Xu, Y.; Lv, L.; Duan, W.; Bai, R.; Meng, Z.; Shao, X. Involvement of the BDNF-TrkB-KCC2 pathway in neuropathic pain after brachial plexus avulsion. Brain Behav. 2022, 12, e2464.
  61. Kitayama, T. The Role of K(+)-Cl(-)-Cotransporter-2 in Neuropathic Pain. Neurochem. Res. 2018, 43, 110–115.
  62. Ji, R.R.; Nackley, A.; Huh, Y.; Terrando, N.; Maixner, W. Neuroinflammation and Central Sensitization in Chronic and Widespread Pain. Anesthesiology 2018, 129, 343–366.
  63. Xiong, H.Y.; Zhang, Z.J.; Wang, X.Q. Bibliometric Analysis of Research on the Comorbidity of Pain and Inflammation. Pain Res. Manag. 2021, 2021, 6655211.
  64. Ji, R.R.; Chamessian, A.; Zhang, Y.Q. Pain regulation by non-neuronal cells and inflammation. Science 2016, 354, 572–577.
  65. Bathina, S.; Das, U.N. Brain-derived neurotrophic factor and its clinical implications. Arch. Med. Sci. 2015, 11, 1164–1178.
  66. Zhou, T.T.; Wu, J.R.; Chen, Z.Y.; Liu, Z.X.; Miao, B. Effects of dexmedetomidine on P2X4Rs, p38-MAPK and BDNF in spinal microglia in rats with spared nerve injury. Brain Res. 2014, 1568, 21–30.
  67. Coull, J.A.; Beggs, S.; Boudreau, D.; Boivin, D.; Tsuda, M.; Inoue, K.; Gravel, C.; Salter, M.W.; De Koninck, Y. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 2005, 438, 1017–1021.
  68. Ferrini, F.; Trang, T.; Mattioli, T.A.; Laffray, S.; Del’Guidice, T.; Lorenzo, L.E.; Castonguay, A.; Doyon, N.; Zhang, W.; Godin, A.G.; et al. Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl(-) homeostasis. Nat. Neurosci. 2013, 16, 183–192.
  69. Marini, A.M.; Jiang, X.; Wu, X.; Tian, F.; Zhu, D.; Okagaki, P.; Lipsky, R.H. Role of brain-derived neurotrophic factor and NF-kappaB in neuronal plasticity and survival: From genes to phenotype. Restor. Neurol. Neurosci. 2004, 22, 121–130.
  70. Mannion, R.J.; Costigan, M.; Decosterd, I.; Amaya, F.; Ma, Q.P.; Holstege, J.C.; Ji, R.R.; Acheson, A.; Lindsay, R.M.; Wilkinson, G.A.; et al. Neurotrophins: Peripherally and centrally acting modulators of tactile stimulus-induced inflammatory pain hypersensitivity. Proc. Natl. Acad. Sci. USA 1999, 96, 9385–9390.
  71. Li, H.; Liu, T.; Sun, J.; Zhao, S.; Wang, X.; Luo, W.; Luo, R.; Shen, W.; Luo, C.; Fu, D. Up-Regulation of ProBDNF/p75(NTR) Signaling in Spinal Cord Drives Inflammatory Pain in Male Rats. J. Inflamm. Res. 2023, 16, 95–107.
  72. Lang, B.C.; Zhang, Z.; Lv, L.Y.; Liu, J.; Wang, T.Y.; Yang, L.H.; Liao, D.Q.; Zhang, W.S.; Wang, T.H. OECs transplantation results in neuropathic pain associated with BDNF regulating ERK activity in rats following cord hemisection. BMC Neurosci. 2013, 14, 80.
  73. Hempstead, B.L. The many faces of p75NTR. Curr. Opin. Neurobiol. 2002, 12, 260–267.
  74. Chao, M.V. Neurotrophins and their receptors: A convergence point for many signalling pathways. Nat. Rev. Neurosci. 2003, 4, 299–309.
  75. Slack, S.E.; Pezet, S.; McMahon, S.B.; Thompson, S.W.; Malcangio, M. Brain-derived neurotrophic factor induces NMDA receptor subunit one phosphorylation via ERK and PKC in the rat spinal cord. Eur. J. Neurosci. 2004, 20, 1769–1778.
  76. Sarchielli, P.; Mancini, M.L.; Floridi, A.; Coppola, F.; Rossi, C.; Nardi, K.; Acciarresi, M.; Pini, L.A.; Calabresi, P. Increased levels of neurotrophins are not specific for chronic migraine: Evidence from primary fibromyalgia syndrome. J. Pain 2007, 8, 737–745.
  77. Jablochkova, A.; Backryd, E.; Kosek, E.; Mannerkorpi, K.; Ernberg, M.; Gerdle, B.; Ghafouri, B. Unaltered low nerve growth factor and high brain-derived neurotrophic factor levels in plasma from patients with fibromyalgia after a 15-week progressive resistance exercise. J. Rehabil. Med. 2019, 51, 779–787.
  78. Haas, L.; Portela, L.V.; Bohmer, A.E.; Oses, J.P.; Lara, D.R. Increased plasma levels of brain derived neurotrophic factor (BDNF) in patients with fibromyalgia. Neurochem. Res. 2010, 35, 830–834.
  79. Simao, A.P.; Mendonca, V.A.; de Oliveira Almeida, T.M.; Santos, S.A.; Gomes, W.F.; Coimbra, C.C.; Lacerda, A.C. Involvement of BDNF in knee osteoarthritis: The relationship with inflammation and clinical parameters. Rheumatol. Int. 2014, 34, 1153–1157.
  80. Laske, C.; Stransky, E.; Eschweiler, G.W.; Klein, R.; Wittorf, A.; Leyhe, T.; Richartz, E.; Kohler, N.; Bartels, M.; Buchkremer, G.; et al. Increased BDNF serum concentration in fibromyalgia with or without depression or antidepressants. J. Psychiatr. Res. 2007, 41, 600–605.
  81. Stefani, L.C.; Leite, F.M.; da Graca, L.T.M.; Zanette, S.A.; de Souza, A.; Castro, S.M.; Caumo, W. BDNF and serum S100B levels according the spectrum of structural pathology in chronic pain patients. Neurosci. Lett. 2019, 706, 105–109.
  82. Nugraha, B.; Korallus, C.; Gutenbrunner, C. Serum level of brain-derived neurotrophic factor in fibromyalgia syndrome correlates with depression but not anxiety. Neurochem. Int. 2013, 62, 281–286.
  83. Zanette, S.A.; Dussan-Sarria, J.A.; Souza, A.; Deitos, A.; Torres, I.L.; Caumo, W. Higher serum S100B and BDNF levels are correlated with a lower pressure-pain threshold in fibromyalgia. Mol. Pain. 2014, 10, 46.
  84. Bidari, A.; Ghavidel-Parsa, B.; Gharibpoor, F. Comparison of the serum brain-derived neurotrophic factor (BDNF) between fibromyalgia and nociceptive pain groups; and effect of duloxetine on the BDNF level. BMC Musculoskelet. Disord. 2022, 23, 411.
  85. Klein, K.; Aeschlimann, A.; Jordan, S.; Gay, R.; Gay, S.; Sprott, H. ATP induced brain-derived neurotrophic factor expression and release from osteoarthritis synovial fibroblasts is mediated by purinergic receptor P2X4. PLoS ONE 2012, 7, e36693.
  86. Grimsholm, O.; Guo, Y.; Ny, T.; Forsgren, S. Expression patterns of neurotrophins and neurotrophin receptors in articular chondrocytes and inflammatory infiltrates in knee joint arthritis. Cells Tissues Organs 2008, 188, 299–309.
  87. Gowler, P.R.W.; Li, L.; Woodhams, S.G.; Bennett, A.J.; Suzuki, R.; Walsh, D.A.; Chapman, V. Peripheral brain-derived neurotrophic factor contributes to chronic osteoarthritis joint pain. Pain 2020, 161, 61–73.
  88. Ferrini, F.; Salio, C.; Boggio, E.M.; Merighi, A. Interplay of BDNF and GDNF in the Mature Spinal Somatosensory System and Its Potential Therapeutic Relevance. Curr. Neuropharmacol. 2021, 19, 1225–1245.
  89. Charlton, T.; Prowse, N.; McFee, A.; Heiratifar, N.; Fortin, T.; Paquette, C.; Hayley, S. Brain-derived neurotrophic factor (BDNF) has direct anti-inflammatory effects on microglia. Front. Cell Neurosci. 2023, 17, 1188672.
  90. Hu, X.M.; Cao, S.B.; Zhang, H.L.; Lyu, D.M.; Chen, L.P.; Xu, H.; Pan, Z.Q.; Shen, W. Downregulation of miR-219 enhances brain-derived neurotrophic factor production in mouse dorsal root ganglia to mediate morphine analgesic tolerance by upregulating CaMKIIgamma. Mol. Pain 2016, 12, 1744806916666283.
  91. Cejas, P.J.; Martinez, M.; Karmally, S.; McKillop, M.; McKillop, J.; Plunkett, J.A.; Oudega, M.; Eaton, M.J. Lumbar transplant of neurons genetically modified to secrete brain-derived neurotrophic factor attenuates allodynia and hyperalgesia after sciatic nerve constriction. Pain 2000, 86, 195–210.
  92. Jiang, Y.; Wei, N.; Zhu, J.; Lu, T.; Chen, Z.; Xu, G.; Liu, X. Effects of brain-derived neurotrophic factor on local inflammation in experimental stroke of rat. Mediat. Inflamm. 2010, 2010, 372423.
  93. Barrientos, R.M.; Sprunger, D.B.; Campeau, S.; Watkins, L.R.; Rudy, J.W.; Maier, S.F. BDNF mRNA expression in rat hippocampus following contextual learning is blocked by intrahippocampal IL-1beta administration. J. Neuroimmunol. 2004, 155, 119–126.
  94. Wang, M.; Pan, W.; Xu, Y.; Zhang, J.; Wan, J.; Jiang, H. Microglia-Mediated Neuroinflammation: A Potential Target for the Treatment of Cardiovascular Diseases. J. Inflamm. Res. 2022, 15, 3083–3094.
  95. Egan, M.F.; Kojima, M.; Callicott, J.H.; Goldberg, T.E.; Kolachana, B.S.; Bertolino, A.; Zaitsev, E.; Gold, B.; Goldman, D.; Dean, M.; et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003, 112, 257–269.
  96. Yu, Y.B.; Zuo, X.L.; Zhao, Q.J.; Chen, F.X.; Yang, J.; Dong, Y.Y.; Wang, P.; Li, Y.Q. Brain-derived neurotrophic factor contributes to abdominal pain in irritable bowel syndrome. Gut 2012, 61, 685–694.
  97. Vossen, H.; Kenis, G.; Rutten, B.; van Os, J.; Hermens, H.; Lousberg, R. The genetic influence on the cortical processing of experimental pain and the moderating effect of pain status. PLoS ONE 2010, 5, e13641.
  98. Zhao, M.; Chen, L.; Yang, J.; Han, D.; Fang, D.; Qiu, X.; Yang, X.; Qiao, Z.; Ma, J.; Wang, L.; et al. BDNF Val66Met polymorphism, life stress and depression: A meta-analysis of gene-environment interaction. J. Affect. Disord. 2018, 227, 226–235.
  99. de Oliveira Franco, A.; de Oliveira Venturini, G.; da Silveira Alves, C.F.; Alves, R.L.; Vicuna, P.; Ramalho, L.; Tomedi, R.; Bruck, S.M.; Torres, I.L.S.; Fregni, F.; et al. Functional connectivity response to acute pain assessed by fNIRS is associated with BDNF genotype in fibromyalgia: An exploratory study. Sci. Rep. 2022, 12, 18831.
  100. da Silveira Alves, C.F.; Caumo, W.; Silvestri, J.M.; Zortea, M.; Dos Santos, V.S.; Cardoso, D.F.; Regner, A.; de Souza, A.H.; Simon, D. Pain catastrophizing is associated with the Val66Met polymorphism of the brain-derived neurotrophic factor in fibromyalgia. Adv. Rheumatol. 2020, 60, 39.
  101. Tian, Y.; Liu, X.; Jia, M.; Yu, H.; Lichtner, P.; Shi, Y.; Meng, Z.; Kou, S.; Ho, I.H.T.; Jia, B.; et al. Targeted Genotyping Identifies Susceptibility Locus in Brain-derived Neurotrophic Factor Gene for Chronic Postsurgical Pain. Anesthesiology 2018, 128, 587–597.
  102. Lamy, J.C.; Boakye, M. BDNF Val66Met polymorphism alters spinal DC stimulation-induced plasticity in humans. J. Neurophysiol. 2013, 110, 109–116.
  103. Cheeran, B.; Talelli, P.; Mori, F.; Koch, G.; Suppa, A.; Edwards, M.; Houlden, H.; Bhatia, K.; Greenwood, R.; Rothwell, J.C. A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS. J. Physiol. 2008, 586, 5717–5725.
  104. Kerr, J.I.; Burri, A. Genetic and epigenetic epidemiology of chronic widespread pain. J. Pain Res. 2017, 10, 2021–2029.
  105. D’Agnelli, S.; Arendt-Nielsen, L.; Gerra, M.C.; Zatorri, K.; Boggiani, L.; Baciarello, M.; Bignami, E. Fibromyalgia: Genetics and epigenetics insights may provide the basis for the development of diagnostic biomarkers. Mol. Pain 2019, 15, 1744806918819944.
  106. Crow, M.; Denk, F.; McMahon, S.B. Genes and epigenetic processes as prospective pain targets. Genome Med. 2013, 5, 12.
  107. Mauceri, D. Role of Epigenetic Mechanisms in Chronic Pain. Cells 2022, 11, 2613.
  108. Tan, M.; Shen, L.; Hou, Y. Epigenetic modification of BDNF mediates neuropathic pain via miR-30a-3p/EP300 axis in CCI rats. Biosci. Rep. 2020, 40, BSR20194442.
  109. Zhang, L.; Feng, H.; Jin, Y.; Zhan, Y.; Han, Q.; Zhao, X.; Li, P. Long Non-coding RNA LINC01119 Promotes Neuropathic Pain by Stabilizing BDNF Transcript. Front. Mol. Neurosci. 2021, 14, 673669.
  110. Polli, A.; Ghosh, M.; Bakusic, J.; Ickmans, K.; Monteyne, D.; Velkeniers, B.; Bekaert, B.; Godderis, L.; Nijs, J. DNA Methylation and Brain-Derived Neurotrophic Factor Expression Account for Symptoms and Widespread Hyperalgesia in Patients With Chronic Fatigue Syndrome and Comorbid Fibromyalgia. Arthritis Rheumatol. 2020, 72, 1936–1944.
  111. Paoloni-Giacobino, A.; Luthi, F.; Stenz, L.; Le Carre, J.; Vuistiner, P.; Leger, B. Altered BDNF Methylation in Patients with Chronic Musculoskeletal Pain and High Biopsychosocial Complexity. J. Pain Res. 2020, 13, 1289–1296.
  112. Menzies, V.; Lyon, D.E.; Archer, K.J.; Zhou, Q.; Brumelle, J.; Jones, K.H.; Gao, G.; York, T.P.; Jackson-Cook, C. Epigenetic alterations and an increased frequency of micronuclei in women with fibromyalgia. Nurs. Res. Pract. 2013, 2013, 795784.
  113. Xiong, H.Y.; Zheng, J.J.; Wang, X.Q. Non-invasive Brain Stimulation for Chronic Pain: State of the Art and Future Directions. Front. Mol. Neurosci. 2022, 15, 888716.
  114. Knotkova, H.; Hamani, C.; Sivanesan, E.; Le Beuffe, M.F.E.; Moon, J.Y.; Cohen, S.P.; Huntoon, M.A. Neuromodulation for chronic pain. Lancet 2021, 397, 2111–2124.
  115. Xiong, H.Y.; Cao, Y.Q.; Du, S.H.; Yang, Q.H.; He, S.Y.; Wang, X.Q. Effects of High-Definition Transcranial Direct Current Stimulation Targeting the Anterior Cingulate Cortex on the Pain Thresholds: A Randomized Controlled Trial. Pain Med. 2023, 24, 89–98.
  116. Villamar, M.F.; Wivatvongvana, P.; Patumanond, J.; Bikson, M.; Truong, D.Q.; Datta, A.; Fregni, F. Focal modulation of the primary motor cortex in fibromyalgia using 4x1-ring high-definition transcranial direct current stimulation (HD-tDCS): Immediate and delayed analgesic effects of cathodal and anodal stimulation. J. Pain 2013, 14, 371–383.
  117. Khedr, E.M.; Omran, E.A.H.; Ismail, N.M.; El-Hammady, D.H.; Goma, S.H.; Kotb, H.; Galal, H.; Osman, A.M.; Farghaly, H.S.M.; Karim, A.A.; et al. Effects of transcranial direct current stimulation on pain, mood and serum endorphin level in the treatment of fibromyalgia: A double blinded, randomized clinical trial. Brain Stimul. 2017, 10, 893–901.
  118. Kuo, H.I.; Bikson, M.; Datta, A.; Minhas, P.; Paulus, W.; Kuo, M.F.; Nitsche, M.A. Comparing cortical plasticity induced by conventional and high-definition 4 x 1 ring tDCS: A neurophysiological study. Brain Stimul. 2013, 6, 644–648.
  119. Monte-Silva, K.; Kuo, M.F.; Hessenthaler, S.; Fresnoza, S.; Liebetanz, D.; Paulus, W.; Nitsche, M.A. Induction of late LTP-like plasticity in the human motor cortex by repeated non-invasive brain stimulation. Brain Stimul. 2013, 6, 424–432.
  120. Scarabelot, V.L.; de Oliveira, C.; Medeiros, L.F.; de Macedo, I.C.; Cioato, S.G.; Adachi, L.N.S.; Paz, A.H.; de Souza, A.; Caumo, W.; Torres, I.L.S. Transcranial direct-current stimulation reduces nociceptive behaviour in an orofacial pain model. J. Oral Rehabil. 2019, 46, 40–50.
  121. Fritsch, B.; Reis, J.; Martinowich, K.; Schambra, H.M.; Ji, Y.; Cohen, L.G.; Lu, B. Direct current stimulation promotes BDNF-dependent synaptic plasticity: Potential implications for motor learning. Neuron 2010, 66, 198–204.
  122. Lopes, B.C.; Medeiros, L.F.; Silva de Souza, V.; Cioato, S.G.; Medeiros, H.R.; Regner, G.G.; Lino de Oliveira, C.; Fregni, F.; Caumo, W.; Torres, I.L.S. Transcranial direct current stimulation combined with exercise modulates the inflammatory profile and hyperalgesic response in rats subjected to a neuropathic pain model: Long-term effects. Brain Stimul. 2020, 13, 774–782.
  123. Filho, P.R.; Vercelino, R.; Cioato, S.G.; Medeiros, L.F.; de Oliveira, C.; Scarabelot, V.L.; Souza, A.; Rozisky, J.R.; Quevedo Ada, S.; Adachi, L.N.; et al. Transcranial direct current stimulation (tDCS) reverts behavioral alterations and brainstem BDNF level increase induced by neuropathic pain model: Long-lasting effect. Prog. Neuropsychopharmacol. Biol. Psychiatry 2016, 64, 44–51.
  124. Marlatt, M.W.; Potter, M.C.; Lucassen, P.J.; van Praag, H. Running throughout middle-age improves memory function, hippocampal neurogenesis, and BDNF levels in female C57BL/6J mice. Dev. Neurobiol. 2012, 72, 943–952.
  125. Lima, L.V.; Abner, T.S.S.; Sluka, K.A. Does exercise increase or decrease pain? Central mechanisms underlying these two phenomena. J. Physiol. 2017, 595, 4141–4150.
  126. Lee, M.; Moon, W.; Kim, J. Effect of yoga on pain, brain-derived neurotrophic factor, and serotonin in premenopausal women with chronic low back pain. Evid. Based Complement. Altern. Med. 2014, 2014, 203173.
  127. Wang, Y.H.; Zhou, H.H.; Luo, Q.; Cui, S. The effect of physical exercise on circulating brain-derived neurotrophic factor in healthy subjects: A meta-analysis of randomized controlled trials. Brain Behav. 2022, 12, e2544.
  128. Pedersen, B.K. Physical activity and muscle-brain crosstalk. Nat. Rev. Endocrinol. 2019, 15, 383–392.
  129. Di-Bonaventura, S.; Fernandez-Carnero, J.; Matesanz-Garcia, L.; Arribas-Romano, A.; Polli, A.; Ferrer-Pena, R. Effect of Different Physical Therapy Interventions on Brain-Derived Neurotrophic Factor Levels in Chronic Musculoskeletal Pain Patients: A Systematic Review. Life 2023, 13, 163.
  130. Ribeiro, V.G.C.; Mendonca, V.A.; Souza, A.L.C.; Fonseca, S.F.; Camargos, A.C.R.; Lage, V.K.S.; Neves, C.D.C.; Santos, J.M.; Teixeira, L.A.C.; Vieira, E.L.M.; et al. Inflammatory biomarkers responses after acute whole body vibration in fibromyalgia. Braz. J. Med. Biol. Res. 2018, 51, e6775.
  131. Mojtabavi, H.; Shaka, Z.; Momtazmanesh, S.; Ajdari, A.; Rezaei, N. Circulating brain-derived neurotrophic factor as a potential biomarker in stroke: A systematic review and meta-analysis. J. Transl. Med. 2022, 20, 126.
  132. Gutierrez, A.; Corey-Bloom, J.; Thomas, E.A.; Desplats, P. Evaluation of Biochemical and Epigenetic Measures of Peripheral Brain-Derived Neurotrophic Factor (BDNF) as a Biomarker in Huntington’s Disease Patients. Front. Mol. Neurosci. 2019, 12, 335.
  133. Azoulay, D.; Horowitz, N.A. Brain-derived neurotrophic factor as a potential biomarker of chemotherapy-induced peripheral neuropathy and prognosis in haematological malignancies; what we have learned, the challenges and a need for global standardization. Br. J. Haematol. 2020, 191, 17–18.
  134. Gejl, A.K.; Enevold, C.; Bugge, A.; Andersen, M.S.; Nielsen, C.H.; Andersen, L.B. Associations between serum and plasma brain-derived neurotrophic factor and influence of storage time and centrifugation strategy. Sci. Rep. 2019, 9, 9655.
  135. Polacchini, A.; Metelli, G.; Francavilla, R.; Baj, G.; Florean, M.; Mascaretti, L.G.; Tongiorgi, E. A method for reproducible measurements of serum BDNF: Comparison of the performance of six commercial assays. Sci. Rep. 2015, 5, 17989.
  136. Park, D.J.; Kim, S.H.; Nah, S.S.; Lee, J.H.; Kim, S.K.; Lee, Y.A.; Hong, S.J.; Kim, H.S.; Lee, H.S.; Kim, H.A.; et al. Association between brain-derived neurotrophic factor gene polymorphisms and fibromyalgia in a Korean population: A multicenter study. Arthritis Res. Ther. 2018, 20, 220.
  137. Zorina-Lichtenwalter, K.; Meloto, C.B.; Khoury, S.; Diatchenko, L. Genetic predictors of human chronic pain conditions. Neuroscience 2016, 338, 36–62.
Subjects: Anesthesiology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to : , , , , , ,
View Times: 38
Revisions: 2 times (View History)
Update Date: 15 Mar 2024