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Review

The Role of the Brain-Derived Neurotrophic Factor in Chronic Pain: Links to Central Sensitization and Neuroinflammation

by
Huan-Yu Xiong
1,
Jolien Hendrix
1,2,3,
Siobhan Schabrun
4,5,
Arne Wyns
1,
Jente Van Campenhout
1,
Jo Nijs
1,6,7,* and
Andrea Polli
1,2,3
1
Pain in Motion Research Group (PAIN), Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, 1090 Brussels, Belgium
2
Department of Public Health and Primary Care, Centre for Environment & Health, KU Leuven, 3000 Leuven, Belgium
3
Research Foundation—Flanders (FWO), 1000 Brussels, Belgium
4
The School of Physical Therapy, University of Western Ontario, London, ON N6A 3K7, Canada
5
The Gray Centre for Mobility and Activity, Parkwood Institute, London, ON N6A 4V2, Canada
6
Chronic Pain Rehabilitation, Department of Physical Medicine and Physiotherapy, University Hospital Brussels, 1090 Brussels, Belgium
7
Department of Health and Rehabilitation, Unit of Physiotherapy, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 41390 Göterbog, Sweden
*
Author to whom correspondence should be addressed.
Biomolecules 2024, 14(1), 71; https://doi.org/10.3390/biom14010071
Submission received: 30 November 2023 / Revised: 2 January 2024 / Accepted: 3 January 2024 / Published: 5 January 2024
(This article belongs to the Special Issue Brain-Derived Neurotrophic Factor in Health and Diseases)
Browse Figures
Review Reports Versions Notes

Abstract

:
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. Moreover, consistently elevated BDNF levels are observed in various chronic pain disorders. To comprehensively understand the profound impact of BDNF in chronic pain, we delve into its key characteristics, focusing on its role in underlying molecular mechanisms contributing to chronic pain. Additionally, we also explore the potential utility of BDNF as an objective biomarker for chronic pain. This discussion encompasses emerging therapeutic approaches aimed at modulating BDNF expression, offering insights into addressing the intricate complexities of chronic pain.

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.
Here, we offer an up-to-date exploration of the intricate role of BDNF in chronic pain, delving into factors potentially contributing to its pathophysiology, such as CS and neuroinflammation. Additionally, this review discusses the potential of BDNF as an objective biomarker and an innovative therapeutic target. The scope ranges from specific interventions aimed at BDNF expression to indirect approaches targeting its receptors and signaling pathways, providing a comprehensive overview of the current landscape in chronic pain research and potential therapeutic avenues.

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]. Notably, knockout mice lacking BDNF face challenges in reaching adulthood and, when they do, manifest several sensory impairments [24,25].
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 [26]. The pro-BDNF can be subsequently cleaved by extracellular proteases at synapses and converted to mature BDNF [27]. 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 [28]. Conversely, binding to p75NTR receptors may regulate neuronal apoptosis, axonal process pruning, and long-term depression (LTD) [29,30]. The contrasting effects of BDNF/TrkB and BDNF/p75NTR signaling form a delicate “yin-yang” system that finely manipulates neuroplasticity and neuronal excitability [31]. Therefore, maintaining a proper balance between these two forms of BDNF is crucial for optimal brain function. Furthermore, dysregulation of BDNF functions has been implicated in some diseases such as depression, chronic pain, and neurodegenerative conditions [32].
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 [33,34,35], BDNF is also produced, to a lesser extent, in non-neuronal cells such as glial cells and immune cells [36,37]. Available BDNF was found in different regions of the brain, including the neocortex, pyriform cortex, amygdala, hippocampus, claustrum, thalamus, striatum, hypothalamus, and brainstem [33,38]. In addition, circulating BDNF derives from both peripheral and cerebral sources [39,40,41]. Notably, in human studies, serum [42,43,44] and plasma [45] BDNF levels appear to correlate positively with BDNF levels in the brain. Moreover, findings from animal studies suggest a positive correlation between peripheral blood BDNF levels and its concentration in the cerebral cortex, indicating that fluctuations in peripheral blood BDNF levels may reflect changes in the brain [46,47,48,49,50]. However, recent studies comparing cerebrospinal fluid and serum BDNF levels in patients with Alzheimer’s disease have indicated a lack of correlation [51] and that the levels of BDNF in serum or plasma were found to be significantly higher than those in cerebrospinal fluid, possibly due to peripheral synthesis [52].

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 [53]. 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 [54,55]. Consequently, pain stems from profound changes within the CNS, which not only amplifies responses to nociceptive inputs but also fails to suppress painful signals [56].
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 [57]. 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 [58,59]. It is crucial to recognize that CS involves an activity-dependent increase in the excitability of dorsal horn neurons [54], and BDNF contributes to this process by promoting a gradual increase in neuronal excitability and synaptic plasticity in the spinal dorsal horn [60,61,62]. Studies have demonstrated that BDNF can be synthesized and expressed in the dorsal horn neurons, and the activation of BDNF/TrkB signaling leads to a sustained increase in neuronal excitability, potentially contributing to allodynia, hyperalgesia, and spontaneous pain in neuropathic pain models characterized by CS [63,64].
Persistent CS has been described as a maladaptive neuroplasticity process in chronic pain [65,66]. BDNF can regulate synaptic plasticity in an activity-dependent manner, contributing to LTP [67,68]. 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 [69,70,71]. 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 [72]. 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]. In addition, with activation of TrkB receptors, there is a downstream activation of various signaling pathway cascades, including the MEK/mitogen-activated protein kinase (MAPK) pathway [73], phosphatidylinositol 3-kinase/protein kinase B (PI3K/PKB) [74], PI3K/Akt/mammalian target of rapamycin (mTOR) pathway [75], and nuclear factor kappaB (NF-κB) signaling pathways [76]. Each of these processes contributes to the induction and maintenance of CS in different parts of nociceptive pathways by facilitating LTP.
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 [77,78,79,80]. 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 [61,81,82]. Furthermore, Caumo W. et al. [78] demonstrated an inverse correlation between serum BDNF levels and conditioned pain modulation (CPM) in patients with chronic musculoskeletal pain, highlighting BDNF’s involvement in the impairment of the descending inhibitory nociceptive modulation system. Altered CPM is in fact often observed in individuals with persistent pain [83].

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 [84,85]. 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 [86]. These glial mediators can significantly regulate both excitatory and inhibitory synaptic transmission, thereby contributing to CS and enhanced chronic pain states. Moreover, glial mediators can further act on glial and immune cells to facilitate neuroinflammation through autocrine and paracrine routes [87].
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 [88]. For example, microglial activation following peripheral nerve injury upregulates purinergic receptors, especially P2 × 4R, leading to p38-MAPK phosphorylation and subsequent BDNF release [89]. This microglial-derived BDNF has been implicated in facilitating neuropathic pain and morphine hyperalgesia [90,91]. Additionally, evidence from animal studies also indicated that the synthesis and release of BDNF were significantly increased during inflammatory pain [92,93], cancer pain [94], and neuropathic pain [95]. In the context of neuroinflammation, evidence points to a pivotal shift in astrocytic behavior. Astrocytes, once adept at maintaining homeostatic concentrations of glutamate (Glu) and potassium (K+), undergo a transformation wherein they gain the ability to secrete ATP, Glu, and chemokines [96]. This phenomenon contributes to CS and LTP. Glial-derived BDNF may mediate CS by attenuating inhibitory synaptic transmission. As a pain mediator and modulator, BDNF can intricately manipulate excitatory glutamatergic and inhibitory GABAergic/glycinergic signals [97,98].
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 [99]. 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 [100]. 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 [101,102]. 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 [103,104,105]. 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.
Remarkably, the connection between BDNF and neuroinflammation remains an underexplored area of research. The association between neuroinflammation and persistent pain underscores the importance of investigating inflammatory factors, particularly BDNF, as promising therapeutic targets for the management of chronic pain.

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

Emerging evidence from human studies has revealed higher cerebrospinal fluid [106], plasma [107,108,109], and serum [110,111,112,113] levels of BDNF in patients with chronic pain compared to healthy individuals, which were positively correlated with more severe pain symptoms (Table 1). For instance, higher serum BDNF levels were associated with lower pressure pain thresholds in patients with fibromyalgia [113]. Notably, a one-month treatment with duloxetine (an antidepressant) not only alleviated pain but also led to reduced serum BDNF levels [114], supporting a pro-nociceptive role of BDNF in chronic pain. Recent evidence also supports the pro-nociceptive role of BDNF in arthritis pain [115], with higher plasma BDNF levels observed in patients with knee osteoarthritis compared to healthy controls, positively correlating with self-reported pain levels [109]. BDNF and TrkB were identified in nerve fascicles within synovial tissue from both patients with osteoarthritis and animal models of inflammatory arthritis [116,117]. As expected, experimental injection of peripheral BDNF increased pain behavior [117]. In addition, inhibition of BDNF/TrkB signaling in animal models of postherpetic neuralgia attenuated mechanical allodynia, reduced inflammation, and reversed neuronal hyperexcitability [18]. These findings strongly advocate that upregulated BDNF expression in chronic pain is not merely a byproduct, but a pivotal causal factor.
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 [118,119,120]. For instance, preliminary evidence from animal research suggests that the release of BDNF can alleviate allodynia and hyperalgesia induced by chronic constriction injury [121]. Additionally, BDNF shows anti-inflammatory effects on the animal brain [122], and experimentally induced inflammation, such as the infusion of IL-1 into the hippocampus, and diminishes BDNF transcription capacity [123]. 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 [124]. Secondly, the anti-nociceptive effect of BDNF may result from central rather than peripheral actions, as elevated levels of peripheral BDNF have been shown to sensitize primary afferent neurons and promote pain hypersensitivity [125]. Moreover, given the fact that inflammation is accompanied by BDNF release [126], upregulated BDNF expression in the CNS may have an anti-inflammatory effect following early pain exposure, suggesting a more significant role in acute rather than chronic pain. Finally, BDNF’s neuroprotective properties may indirectly contribute to an anti-inflammatory environment. By promoting the survival of neurons and maintaining overall neuronal health, BDNF may reduce the release of inflammatory signals associated with cell damage.
Table 1. Brain-derived neurotrophic factor levels and association with pain in patients with chronic pain.
Table 1. Brain-derived neurotrophic factor levels and association with pain in patients with chronic pain.
ReferenceStudy PopulationSource of BDNF
Measurement		Mean ± SD BDNF Valuesp-ValuesCorrelation with Pain
Polli et al., 2020 [127]Chronic fatigue syndrome and comorbid fibromyalgia (n = 28)
Healthy controls (n = 26)		SerumChronic fatigue syndrome and comorbid fibromyalgia: 17.75 ± 4.48,
Healthy controls: 14.89 ± 3.55 (values in ng/mL)		SigHigher BDNF levels predicted participants’ symptoms and widespread hyperalgesia
Jasim et al., 2020 [128]Chronic temporomandibular disorder myalgia (n = 39)
Healthy controls (n = 39)		PlasmaChronic temporomandibular disorder myalgia: 263.33 ± 245.13,
Healthy controls: 151.81 ± 125.90
(values in pg/mL)		SigNot evaluated
Stefani et al., 2019 [111]Fibromyalgia (n = 117)
Osteoarthritis (n = 88)
Chronic tensional-type headache (n = 33)
Healthy controls (n = 41)		SerumOsteoarthritis: 24.85,
Fibromyalgia: 38.60,
Chronic tensional type headache: 37.22,
Healthy controls: 22.85
(values in pg/mL)		SigNot evaluated
Jablochkova et al., 2019 [107]Fibromyalgia (n = 75)
Healthy controls (n = 25)		PlasmaFibromyalgia: 1553.30,
Healthy controls: 671.6
(values in pg/mL)		SigNo correlation
Caumo et al., 2016 [78]Fibromyalgia (n = 19), osteoarthritis (n = 27),
myofascial pain syndrome (n = 54), healthy controls (n = 14)		SerumFibromyalgia: 50.78 ± 16.06,
Osteoarthritis: 17.91 ± 7.27,
Myofascial pain syndrome: 29.28 ± 20.01,
Healthy controls: 19.00 ± 8.79
(values in ng/mL)		SigHigher BDNF levels were significantly correlated with decreased inhibitory system as assessed through conditioned pain modulation
Deitos et al., 2015 [129]Central sensitivity syndrome absent of structural pathology (n = 81)
Central sensitivity syndrome with persistent nociception (n = 59)
Healthy controls (n = 37)		SerumCentral sensitivity syndrome absent of structural pathology: 49.87 ± 31.86,
Central sensitivity syndrome with persistent nociception: 20.44 ± 8.30,
Healthy controls: 14.09 ± 11.80
(values in ng/mL)		SigNot evaluated
Bidari et al., 2022 [114]Fibromyalgia (n = 53)
Non-fibromyalgia chronic nociceptive pain (n = 60)		SerumNo differences between the two groupsNot SigDecreasing serum BDNF after treatment with duloxetine was associated with the improvement in the disease severity, depression, and pain level
Ranzolin et al., 2016 [130]Fibromyalgia (n = 69)
Healthy controls (n = 61)		SerumNo differences between the two groupsNot SigNot evaluated
Iannuccelli et al., 2022 [131]Fibromyalgia (n = 40)
Healthy controls (n = 40)		SerumFibromyalgia: 3.38 ± 2.49,
Healthy controls: 8.57 ± 3.65
(values in ng/mL)		SigNo correlation
BDNF, brain-derived neurotrophic factor.

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 [132]. The single-nucleotide polymorphism rs6265 in the BDNF gene, located in the 5′-prodomain of immature BDNF protein and often referred to as Val66Met [132,133], has emerged as a key player in shaping pain perception and pain-related symptoms [134,135], and is associated with vulnerability to different chronic pain disorders [136,137,138] (Table 2). The Val/Val genotype has been linked to a distinct propensity for fibromyalgia symptoms and increased pain catastrophizing [137]. Similarly, research has established a connection between individuals carrying the Val allele and an increased susceptibility to chronic postsurgical pain [138], as well as a correlation with the severity of depression [139]. In addition, a recent clinical study in cancer survivors revealed that those with the Met/Met genotype of BDNF rs6265 reported significantly more severe cancer-related neuropathic pain and fatigue than those with other genotypes [140].
BDNF, with its influence on crucial neuronal processes, is subject to complex changes in function due to its polymorphism, particularly in modulating neuroplasticity [68]. 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 [141,142]. Furthermore, in cultured hippocampal neurons, the BDNF protein carrying the Met variant exhibited lower depolarization-induced secretion [134]. Individuals with one or two copies of the BDNF Met allele also appear to exhibit decreased brain plasticity, suggesting that the Met allele may influence mechanisms associated with rectifying dysfunctional circuits involved in the imbalance of excitatory and inhibitory systems in the CNS [78,143,144]. In addition, certain BDNF polymorphisms have an effect on specific aspects of brain function such as default mode network connectivity, which is currently considered to be central in the pathogenesis of fibromyalgia [145,146]. In conclusion, while chronic pain does not stem from a singular gene, genetic studies focusing on BDNF polymorphisms offer valuable insights into potential connections with pain perception and brain plasticity [147,148,149]. These genetic nuances may impact susceptibility to various chronic pain conditions and influence the severity of pain experienced.
Table 2. BDNF Val66Met Polymorphism in patients with chronic pain.
Table 2. BDNF Val66Met Polymorphism in patients with chronic pain.
ReferenceStudy PopulationTissueGenotyping MethodGenotype Model (BDNF rs6265)Main Results
Goto et al., 2023 [140]Female cancer survivors (n = 393)Buccal swabIsolated genomic DNA from buccal cells. The analysis of the BDNF genotype involved using the PCR SNP Genotyping assaysVal/Val (n = 258)
Val/Met (n = 123)
Met/Met (n = 12)		Participants with the Met/Met BDNF genotype reported significantly worse cancer-related fatigue and neuropathic pain.
Álvaro et al., 2022 [136]Fibromyalgia (n = 42)BloodRT-PCRVal/Val (n = 30)
Val/Met (n = 12)		Val/Met genotypes showed higher efficiency of the descending pain modulatory system and lower disability due to pain. FM patients carrying the Val/Met BDNF genotype presented an increased functional connectivity across the motor and prefrontal cortex in response to acute pain associated with differences in acute pain perception and FM.
Yamada et al., 2021 [150]Chronic low back pain (n = 107)BloodRT-PCRVal/Val (n = 81)
Val/Met (n = 26)		No significant associations between the Val66Met genotypes and pain outcomes.
Camila et al., 2020 [137]Fibromyalgia (n = 108) Healthy controls (n = 108)BloodRT-PCRVal/Val (n = 87)
Val/Met (n = 21)		Val allele was significantly more frequent in patients with FM compared to the healthy controls. The BDNF Val/Val homozygotes are a potential genetic risk factor associated with higher scores in the Pain Catastrophizing Scale domains: magnification and rumination in patients with FM.
Reddy et al., 2014 [151]Chronic abdominal pain (n = 18)
Healthy controls (n = 31)		BloodRT-PCRVal/Val (n = 13)
Met allele (n = 5)		No significant associations observed with regard to BDNF genotypes with sleep quality or pain grouping.
BDNF, brain-derived neurotrophic factor; RT-PCR, real-time polymerase chain reaction; SNP, single nucleotide polymorphism; FM, fibromyalgia.

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 [152,153]. 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 [154,155]. Recent studies revealed that epigenetic mechanisms, including histone acetylation [156], non-coding RNAs [156,157], and DNA methylation [127,158,159], can influence the expression of BDNF (Figure 2, Table 3). These epigenetic modifications may contribute to the pathogenesis and symptomatology of chronic pain.
Polli et al. [127] reported that patients with chronic fatigue syndrome and comorbid fibromyalgia exhibited lower DNA methylation levels in the BDNF gene compared to healthy individuals. DNA hypomethylation was associated with elevated serum BDNF expression, which in turn correlated with symptoms and hyperalgesia in these patients [127]. Additionally, Tao et al. [126] suggested that persistent inflammation could epigenetically upregulate BDNF protein expression, in turn increasing hypersensitivity and pain levels. Recent studies have shown that miRNAs can regulate BDNF expression and function. For example, findings from animal research indicate that miR-206-3p regulates BDNF expression through a conserved binding site in its 3′-UTR [160]. Notably, a study demonstrated that electroacupuncture alleviated neuropathic pain induced by chronic constriction injury by increasing miR-206-3p expression and inhibiting BDNF overexpression [161]. However, administration of the miR-206-3p inhibitor partially impaired the analgesic effect of electroacupuncture and the level of BDNF was elevated as well.
It is crucial to note that BDNF is highly susceptible to environmental influences (e.g., physical exercise, diet and nutrition, stress, and sleep patterns), which can, in turn, impact gene expression. For example, regular aerobic exercise has been associated with increased levels of BDNF [162], while chronic stress and elevated cortisol levels correlate with a reduction in BDNF expression [163]. Additionally, disrupted sleep patterns and chronic sleep deprivation can negatively impact BDNF levels [164]. From a biological perspective, an organism’s responses to the external environment are mirrored in epigenetic changes, influencing neuronal activity, such as cortical excitability and synaptic plasticity, thereby triggering behavioral alterations [165]. Moreover, alterations in chromatin structure represent one mechanism through which pain gradually transforms into the pathological processes of neuroinflammation, CS, and ultimately chronic pain [166].

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 [167,168,169]. 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 [170,171]. While the exact mechanisms underlying these effects remain unclear, accumulating research suggests that the impact of tDCS may be neuroplasticity-state-dependent [172,173], with alterations in BDNF levels predicting the effects of tDCS on behavioral outcomes [174,175]. In other words, the analgesic effect of tDCS may depend on changes in endogenous BDNF levels [176,177], as BDNF is a driving force behind neuroplasticity [66]. A recent clinical study in patients with knee osteoarthritis revealed that active tDCS induced a significant reduction in both serum BDNF levels and pain intensity, compared to sham tDCS [178]. Consistent with previous preclinical studies, active tDCS reverted behavioral alterations associated with neuropathic pain, and decreased both serum and cerebral cortex BDNF levels [177]. Similarly, active tDCS alleviated nociceptive hypersensitivity induced by ovariectomy and reduced hippocampal BDNF levels [179]. These findings not only demonstrate the analgesic potential of tDCS but also suggest that tDCS-induced changes in neural circuits involved in pain processing correspond to alterations in BDNF levels, wherein reduced BDNF levels might directly contribute to pain relief.
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 [180,181,182]. Similarly promising outcomes have been observed in healthy individuals [183]. 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 [184,185,186]. Notably, among neurotrophins, BDNF appears particularly responsive to exercise and physical activities [187]. Furthermore, the interplay of physical activity/inactivity extends to influencing epigenetic modifications, potentially inducing changes in BDNF expression [188,189].
In animal studies, the administration of a BDNF inhibitor or TrkB inhibitor was shown to reduce pain-like behavior. This suggests that BDNF-blocking therapies offer a viable therapeutic approach, targeting BDNF and/or its receptors through both pharmacological and non-pharmacological approaches. The TrkB receptor, serving as an endogenous receptor for BDNF and abundantly expressed in primary sensory neurons, is upregulated in chronic pain states, implicating BDNF/TrkB signaling in the process of CS [93,190]. TrkB-Fc, a chimeric compound sequestering endogenous BDNF, has shown promise in blocking BDNF effects on synaptic plasticity both in vivo and in neuropathic pain models [191]. Furthermore, spinal administration of TrkB-Fc has been reported to successfully reverse pain behavior in neuropathic pain models [192].
Medications can influence BDNF levels through various mechanisms, one of which is to reduce inflammation by targeting specific pro-inflammatory cytokines [193,194]. Steroids, commonly used to alleviate inflammation in immune-mediated diseases, have been demonstrated to inhibit BDNF expression in neurons [193]. While the pharmacological manipulation of BDNF expression holds promise for novel treatments, navigating the complex effects of different medications—often necessitating multiple drugs for patients—adds intricacy to the assessment of the final outcome. Notably, the potential adverse effects of blocking BDNF must be carefully considered, given its neuroprotective role in promoting neuronal growth and survival. Consequently, finely tuning BDNF expression, location, and secretion becomes imperative to fulfill its complex duties. A comprehensive understanding of these processes holds the key to developing new molecules and treatments for diseases associated with BDNF.

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 [195,196,197], 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 [47,198]. Measuring circulatory BDNF in peripheral blood, specifically in serum and plasma, provides a reliable and easily accessible method for sample collection with minimal disadvantages for patients [199].
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 [137,145,200]. 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. Additionally, advancements in genomic technologies, like next-generation sequencing, could provide a more comprehensive analysis of multiple genetic factors, including BDNF polymorphisms, in a single test. Despite these advancements, it is crucial to acknowledge the intricate nature of chronic pain, which results from a complex interplay of genetic, environmental, and psychological factors. While certain genetic variations may contribute to an individual’s susceptibility to pain or influence their responsiveness to pain treatments, it is improbable that a single genetic polymorphism, such as one related to BDNF, can conclusively pinpoint or define a chronic pain condition. Future research endeavors should strive to integrate different genetic risk factors with patient characteristics and clinical and psychological parameters to comprehensively address the multifaceted nature of chronic pain disorders.
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.

5. Conclusions and Future Directions

The exploration of perpetuating factors in pain pathophysiology and their potential as therapeutic targets is crucial, given that existing treatments for patients with persistent pain, while effective, often fall short of expectations. CS is a form of maladaptive neuroplasticity underlying different chronic pain conditions and BDNF is a driving force behind neuroplasticity, influencing optimal brain function. This maladaptive neuroplasticity has been observed in the literature in subjects with similar characteristics. In this sense, it is possible to find therapies that promote the correct adaptation of this induced plasticity, thus providing a way to improve pain and functional recovery in individuals with persistent pain. Several studies have reported altered levels of both brain and peripheral BDNF in pain populations. However, the exact pathophysiological mechanisms driving these changes remain incompletely understood. The existing evidence does not conclusively determine whether alterations in BDNF levels are a cause or a consequence of chronic pain. Therefore, future research directions should prioritize elucidating the multifaceted role of BDNF in chronic pain, particularly given its nuanced actions dependent on pain type, site of expression/secretion, receptor type, and gene polymorphisms. This review also delves into BDNF polymorphisms and epigenetic regulation of BDNF expression within the context of chronic pain. Currently, most evidence comes from cross-sectional and preclinical studies. To comprehensively understand the dynamics of BDNF expression via epigenetic regulation in various chronic pain conditions, further research with larger sample sizes and longitudinal studies in pain populations is imperative. This approach will facilitate a more in-depth exploration of the intricate interplay among genetics, epigenetic modifications, and BDNF in the development and persistence of chronic pain.

Author Contributions

Conceptualization, J.N., A.P. and H.-Y.X.; methodology, J.N. and H.-Y.X.; validation, J.N., A.P. and S.S.; resources, H.-Y.X.; writing—original draft preparation, H.-Y.X.; writing—review and editing, J.N., S.S., A.P., J.H., A.W., J.V.C. and H.-Y.X.; visualization, H.-Y.X.; supervision, J.N., A.P. and S.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the China Scholarship Council (CSC202308310100) to H.-Y.X. and A.P. was funded by the Research Foundation—Flanders (FWO; FWOTM1051). J.H. was funded by the Research Foundation—Flanders (FWO; FWOTM1069). A.W. was funded by the Berekuyl Academy (The Netherlands) chair awarded to the VUB.

Acknowledgments

The figures were created with BioRender.com, accessed on 30 November 2023.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  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. [Google Scholar] [CrossRef] [PubMed]
  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. [Google Scholar] [CrossRef] [PubMed]
  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. [Google Scholar] [CrossRef] [PubMed]
  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. [Google Scholar] [CrossRef] [PubMed]
  5. Bannister, K.; Sachau, J.; Baron, R.; Dickenson, A.H. Neuropathic Pain: Mechanism-Based Therapeutics. Annu. Rev. Pharmacol. Toxicol. 2020, 60, 257–274. [Google Scholar] [CrossRef] [PubMed]
  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. [Google Scholar] [CrossRef] [PubMed]
  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. [Google Scholar] [CrossRef] [PubMed]
  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. [Google Scholar] [CrossRef]
  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. [Google Scholar] [CrossRef]
  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. [Google Scholar] [CrossRef]
  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. [Google Scholar] [CrossRef] [PubMed]
  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. [Google Scholar] [CrossRef] [PubMed]
  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. [Google Scholar] [CrossRef] [PubMed]
  14. Kuner, R.; Flor, H. Structural plasticity and reorganisation in chronic pain. Nat. Rev. Neurosci. 2016, 18, 20–30. [Google Scholar] [CrossRef] [PubMed]
  15. Smith, P.A. BDNF: No gain without pain? Neuroscience 2014, 283, 107–123. [Google Scholar] [CrossRef] [PubMed]
  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. [Google Scholar] [CrossRef] [PubMed]
  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. [Google Scholar] [CrossRef] [PubMed]
  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. [Google Scholar] [CrossRef]
  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. [Google Scholar] [CrossRef]
  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. [Google Scholar] [CrossRef]
  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. [Google Scholar] [CrossRef] [PubMed]
  22. Park, H.; Poo, M.M. Neurotrophin regulation of neural circuit development and function. Nat. Rev. Neurosci. 2013, 14, 7–23. [Google Scholar] [CrossRef] [PubMed]
  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. [Google Scholar] [CrossRef] [PubMed]
  24. Ernfors, P.; Lee, K.F.; Jaenisch, R. Mice lacking brain-derived neurotrophic factor develop with sensory deficits. Nature 1994, 368, 147–150. [Google Scholar] [CrossRef] [PubMed]
  25. Jones, K.R.; Farinas, I.; Backus, C.; Reichardt, L.F. Targeted disruption of the BDNF gene perturbs brain and sensory neuron development but not motor neuron development. Cell 1994, 76, 989–999. [Google Scholar] [CrossRef] [PubMed]
  26. Hempstead, B.L. Brain-Derived Neurotrophic Factor: Three Ligands, Many Actions. Trans. Am. Clin. Climatol. Assoc. 2015, 126, 9–19. [Google Scholar] [PubMed]
  27. 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. [Google Scholar] [CrossRef] [PubMed]
  28. 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. [Google Scholar] [CrossRef]
  29. 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. [Google Scholar] [CrossRef]
  30. 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. [Google Scholar] [CrossRef]
  31. Lu, B.; Pang, P.T.; Woo, N.H. The yin and yang of neurotrophin action. Nat. Rev. Neurosci. 2005, 6, 603–614. [Google Scholar] [CrossRef] [PubMed]
  32. Sochal, M.; Ditmer, M.; Gabryelska, A.; Bialasiewicz, P. The Role of Brain-Derived Neurotrophic Factor in Immune-Related Diseases: A Narrative Review. J. Clin. Med. 2022, 11, 6023. [Google Scholar] [CrossRef] [PubMed]
  33. 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. [Google Scholar] [CrossRef] [PubMed]
  34. 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. [Google Scholar] [CrossRef] [PubMed]
  35. 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. [Google Scholar] [CrossRef] [PubMed]
  36. 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. [Google Scholar] [CrossRef] [PubMed]
  37. Taves, S.; Berta, T.; Chen, G.; Ji, R.R. Microglia and spinal cord synaptic plasticity in persistent pain. Neural Plast. 2013, 2013, 753656. [Google Scholar] [CrossRef]
  38. 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. [Google Scholar] [CrossRef]
  39. 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. [Google Scholar] [CrossRef]
  40. 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. [Google Scholar] [CrossRef]
  41. 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. [Google Scholar] [CrossRef] [PubMed]
  42. Rasmussen, P.; Brassard, P.; Adser, H.; Pedersen, M.V.; Leick, L.; Hart, E.; Secher, N.H.; Pedersen, B.K.; Pilegaard, H. Evidence for a release of brain-derived neurotrophic factor from the brain during exercise. Exp. Physiol. 2009, 94, 1062–1069. [Google Scholar] [CrossRef] [PubMed]
  43. Dawood, T.; Anderson, J.; Barton, D.; Lambert, E.; Esler, M.; Hotchkin, E.; Haikerwal, D.; Kaye, D.; Lambert, G. Reduced overflow of BDNF from the brain is linked with suicide risk in depressive illness. Mol. Psychiatry 2007, 12, 981–983. [Google Scholar] [CrossRef] [PubMed]
  44. Pan, W.; Banks, W.A.; Fasold, M.B.; Bluth, J.; Kastin, A.J. Transport of brain-derived neurotrophic factor across the blood-brain barrier. Neuropharmacology 1998, 37, 1553–1561. [Google Scholar] [CrossRef] [PubMed]
  45. Pillai, A.; Kale, A.; Joshi, S.; Naphade, N.; Raju, M.S.; Nasrallah, H.; Mahadik, S.P. Decreased BDNF levels in CSF of drug-naive first-episode psychotic subjects: Correlation with plasma BDNF and psychopathology. Int. J. Neuropsychopharmacol. 2010, 13, 535–539. [Google Scholar] [CrossRef] [PubMed]
  46. Klein, A.B.; Williamson, R.; Santini, M.A.; Clemmensen, C.; Ettrup, A.; Rios, M.; Knudsen, G.M.; Aznar, S. Blood BDNF concentrations reflect brain-tissue BDNF levels across species. Int. J. Neuropsychopharmacol. 2011, 14, 347–353. [Google Scholar] [CrossRef] [PubMed]
  47. 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. [Google Scholar] [CrossRef]
  48. Karege, F.; Schwald, M.; Cisse, M. Postnatal developmental profile of brain-derived neurotrophic factor in rat brain and platelets. Neurosci. Lett. 2002, 328, 261–264. [Google Scholar] [CrossRef]
  49. Poduslo, J.F.; Curran, G.L. Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF. Brain Res. Mol. Brain Res. 1996, 36, 280–286. [Google Scholar] [CrossRef]
  50. Angelucci, F.; Gelfo, F.; De Bartolo, P.; Caltagirone, C.; Petrosini, L. BDNF concentrations are decreased in serum and parietal cortex in immunotoxin 192 IgG-Saporin rat model of cholinergic degeneration. Neurochem. Int. 2011, 59, 1–4. [Google Scholar] [CrossRef]
  51. Mori, Y.; Tsuji, M.; Oguchi, T.; Kasuga, K.; Kimura, A.; Futamura, A.; Sugimoto, A.; Kasai, H.; Kuroda, T.; Yano, S.; et al. Serum BDNF as a Potential Biomarker of Alzheimer’s Disease: Verification Through Assessment of Serum, Cerebrospinal Fluid, and Medial Temporal Lobe Atrophy. Front. Neurol. 2021, 12, 653267. [Google Scholar] [CrossRef] [PubMed]
  52. Faria, M.C.; Goncalves, G.S.; Rocha, N.P.; Moraes, E.N.; Bicalho, M.A.; Gualberto Cintra, M.T.; Jardim de Paula, J.; Jose Ravic de Miranda, L.F.; Clayton de Souza Ferreira, A.; Teixeira, A.L.; et al. Increased plasma levels of BDNF and inflammatory markers in Alzheimer’s disease. J. Psychiatr. Res. 2014, 53, 166–172. [Google Scholar] [CrossRef] [PubMed]
  53. Meacham, K.; Shepherd, A.; Mohapatra, D.P.; Haroutounian, S. Neuropathic Pain: Central vs. Peripheral Mechanisms. Curr. Pain. Headache Rep. 2017, 21, 28. [Google Scholar] [CrossRef] [PubMed]
  54. Latremoliere, A.; Woolf, C.J. Central sensitization: A generator of pain hypersensitivity by central neural plasticity. J. Pain 2009, 10, 895–926. [Google Scholar] [CrossRef] [PubMed]
  55. 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. [Google Scholar] [CrossRef] [PubMed]
  56. Woolf, C.J.; Salter, M.W. Neuronal plasticity: Increasing the gain in pain. Science 2000, 288, 1765–1769. [Google Scholar] [CrossRef] [PubMed]
  57. 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. [Google Scholar] [CrossRef]
  58. 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. [Google Scholar] [CrossRef]
  59. 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. [Google Scholar] [CrossRef]
  60. 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. [Google Scholar] [CrossRef]
  61. 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. [Google Scholar] [CrossRef] [PubMed]
  62. 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. [Google Scholar] [CrossRef] [PubMed]
  63. Ding, X.; Cai, J.; Li, S.; Liu, X.D.; Wan, Y.; Xing, G.G. BDNF contributes to the development of neuropathic pain by induction of spinal long-term potentiation via SHP2 associated GluN2B-containing NMDA receptors activation in rats with spinal nerve ligation. Neurobiol. Dis. 2015, 73, 428–451. [Google Scholar] [CrossRef] [PubMed]
  64. Zhou, W.; Xie, Z.; Li, C.; Xing, Z.; Xie, S.; Li, M.; Yao, J. Driving effect of BDNF in the spinal dorsal horn on neuropathic pain. Neurosci. Lett. 2021, 756, 135965. [Google Scholar] [CrossRef] [PubMed]
  65. Woolf, C.J. Central sensitization: Implications for the diagnosis and treatment of pain. Pain 2011, 152, S2–S15. [Google Scholar] [CrossRef] [PubMed]
  66. 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. [Google Scholar] [CrossRef] [PubMed]
  67. Wang, C.S.; Kavalali, E.T.; Monteggia, L.M. BDNF signaling in context: From synaptic regulation to psychiatric disorders. Cell 2022, 185, 62–76. [Google Scholar] [CrossRef] [PubMed]
  68. 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. [Google Scholar] [CrossRef]
  69. Zhuo, M. A synaptic model for pain: Long-term potentiation in the anterior cingulate cortex. Mol. Cells 2007, 23, 259–271. [Google Scholar] [CrossRef]
  70. 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. [Google Scholar] [CrossRef]
  71. 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. [Google Scholar] [CrossRef] [PubMed]
  72. 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. [Google Scholar] [CrossRef] [PubMed]
  73. Obata, K.; Noguchi, K. MAPK activation in nociceptive neurons and pain hypersensitivity. Life Sci. 2004, 74, 2643–2653. [Google Scholar] [CrossRef] [PubMed]
  74. Saw, G.; Krishna, K.; Gupta, N.; Soong, T.W.; Mallilankaraman, K.; Sajikumar, S.; Dheen, S.T. Epigenetic regulation of microglial phosphatidylinositol 3-kinase pathway involved in long-term potentiation and synaptic plasticity in rats. Glia 2020, 68, 656–669. [Google Scholar] [CrossRef] [PubMed]
  75. Zhang, H.; Li, Y.; de Carvalho-Barbosa, M.; Kavelaars, A.; Heijnen, C.J.; Albrecht, P.J.; Dougherty, P.M. Dorsal Root Ganglion Infiltration by Macrophages Contributes to Paclitaxel Chemotherapy-Induced Peripheral Neuropathy. J. Pain 2016, 17, 775–786. [Google Scholar] [CrossRef] [PubMed]
  76. Pham, T.L.; Noh, C.; Neupane, C.; Sharma, R.; Shin, H.J.; Park, K.D.; Lee, C.J.; Kim, H.W.; Lee, S.Y.; Park, J.B. MAO-B Inhibitor, KDS2010, Alleviates Spinal Nerve Ligation-induced Neuropathic Pain in Rats Through Competitively Blocking the BDNF/TrkB/NR2B Signaling. J. Pain 2022, 23, 2092–2109. [Google Scholar] [CrossRef] [PubMed]
  77. Hollins, M.; Bryen, C.P.; Taylor, D. Effects of chronic pain history on perceptual and cognitive inhibition. Exp. Brain Res. 2020, 238, 321–332. [Google Scholar] [CrossRef]
  78. 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. [Google Scholar] [CrossRef]
  79. 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. [Google Scholar] [CrossRef]
  80. 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. [Google Scholar] [CrossRef]
  81. 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. [Google Scholar] [CrossRef] [PubMed]
  82. Kitayama, T. The Role of K(+)-Cl(-)-Cotransporter-2 in Neuropathic Pain. Neurochem. Res. 2018, 43, 110–115. [Google Scholar] [CrossRef] [PubMed]
  83. Lewis, G.N.; Rice, D.A.; McNair, P.J. Conditioned pain modulation in populations with chronic pain: A systematic review and meta-analysis. J. Pain 2012, 13, 936–944. [Google Scholar] [CrossRef] [PubMed]
  84. 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. [Google Scholar] [CrossRef] [PubMed]
  85. 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. [Google Scholar] [CrossRef] [PubMed]
  86. Ji, R.R.; Chamessian, A.; Zhang, Y.Q. Pain regulation by non-neuronal cells and inflammation. Science 2016, 354, 572–577. [Google Scholar] [CrossRef] [PubMed]
  87. Ji, R.R.; Xu, Z.Z.; Gao, Y.J. Emerging targets in neuroinflammation-driven chronic pain. Nat. Rev. Drug Discov. 2014, 13, 533–548. [Google Scholar] [CrossRef] [PubMed]
  88. Bathina, S.; Das, U.N. Brain-derived neurotrophic factor and its clinical implications. Arch. Med. Sci. 2015, 11, 1164–1178. [Google Scholar] [CrossRef]
  89. 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. [Google Scholar] [CrossRef]
  90. 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. [Google Scholar] [CrossRef]
  91. 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. [Google Scholar] [CrossRef] [PubMed]
  92. Kras, J.V.; Weisshaar, C.L.; Quindlen, J.; Winkelstein, B.A. Brain-derived neurotrophic factor is upregulated in the cervical dorsal root ganglia and spinal cord and contributes to the maintenance of pain from facet joint injury in the rat. J. Neurosci. Res. 2013, 91, 1312–1321. [Google Scholar] [CrossRef] [PubMed]
  93. Thibault, K.; Lin, W.K.; Rancillac, A.; Fan, M.; Snollaerts, T.; Sordoillet, V.; Hamon, M.; Smith, G.M.; Lenkei, Z.; Pezet, S. BDNF-dependent plasticity induced by peripheral inflammation in the primary sensory and the cingulate cortex triggers cold allodynia and reveals a major role for endogenous BDNF as a tuner of the affective aspect of pain. J. Neurosci. 2014, 34, 14739–14751. [Google Scholar] [CrossRef] [PubMed]
  94. Tomotsuka, N.; Kaku, R.; Obata, N.; Matsuoka, Y.; Kanzaki, H.; Taniguchi, A.; Muto, N.; Omiya, H.; Itano, Y.; Sato, T.; et al. Up-regulation of brain-derived neurotrophic factor in the dorsal root ganglion of the rat bone cancer pain model. J. Pain Res. 2014, 7, 415–423. [Google Scholar] [CrossRef] [PubMed]
  95. Vanelderen, P.; Rouwette, T.; Kozicz, T.; Roubos, E.; Van Zundert, J.; Heylen, R.; Vissers, K. The role of brain-derived neurotrophic factor in different animal models of neuropathic pain. Eur. J. Pain 2010, 14, 473.e1–473.e9. [Google Scholar] [CrossRef] [PubMed]
  96. Ji, R.R.; Berta, T.; Nedergaard, M. Glia and pain: Is chronic pain a gliopathy? Pain 2013, 154 (Suppl. 1), S10–S28. [Google Scholar] [CrossRef]
  97. Trang, T.; Beggs, S.; Salter, M.W. Brain-derived neurotrophic factor from microglia: A molecular substrate for neuropathic pain. Neuron Glia Biol. 2011, 7, 99–108. [Google Scholar] [CrossRef]
  98. Merighi, A.; Salio, C.; Ghirri, A.; Lossi, L.; Ferrini, F.; Betelli, C.; Bardoni, R. BDNF as a pain modulator. Prog. Neurobiol. 2008, 85, 297–317. [Google Scholar] [CrossRef]
  99. 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. [Google Scholar]
  100. 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. [Google Scholar] [CrossRef]
  101. 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. [Google Scholar] [CrossRef] [PubMed]
  102. 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. [Google Scholar] [CrossRef] [PubMed]
  103. Hempstead, B.L. The many faces of p75NTR. Curr. Opin. Neurobiol. 2002, 12, 260–267. [Google Scholar] [CrossRef] [PubMed]
  104. Chao, M.V. Neurotrophins and their receptors: A convergence point for many signalling pathways. Nat. Rev. Neurosci. 2003, 4, 299–309. [Google Scholar] [CrossRef] [PubMed]
  105. 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. [Google Scholar] [CrossRef] [PubMed]
  106. 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. [Google Scholar] [CrossRef]
  107. 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. [Google Scholar] [CrossRef] [PubMed]
  108. 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. [Google Scholar] [CrossRef]
  109. 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. [Google Scholar] [CrossRef]
  110. 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. [Google Scholar] [CrossRef]
  111. 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. [Google Scholar] [CrossRef] [PubMed]
  112. 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. [Google Scholar] [CrossRef] [PubMed]
  113. 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. [Google Scholar] [CrossRef] [PubMed]
  114. 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. [Google Scholar] [CrossRef]
  115. 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. [Google Scholar] [CrossRef]
  116. 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. [Google Scholar] [CrossRef]
  117. 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. [Google Scholar] [CrossRef]
  118. 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. [Google Scholar] [CrossRef]
  119. 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. [Google Scholar] [CrossRef]
  120. 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. [Google Scholar] [CrossRef]
  121. 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. [Google Scholar] [CrossRef] [PubMed]
  122. 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. [Google Scholar] [CrossRef] [PubMed]
  123. 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. [Google Scholar] [CrossRef] [PubMed]
  124. 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. [Google Scholar] [CrossRef] [PubMed]
  125. Finamor, F.; Scarabelot, V.L.; Medeiros, L.F.; Stein, D.J.; da Silva, M.D.; Callai, E.; Caumo, W.; de Souza, A.; Torres, I.L.S. Involvement of GABAergic, glutamatergic, opioidergic, and brain-derived neurotrophic factor systems in the trigeminal neuropathic pain process. Neurosci. Lett. 2023, 793, 136970. [Google Scholar] [CrossRef] [PubMed]
  126. Tao, W.; Chen, Q.; Zhou, W.; Wang, Y.; Wang, L.; Zhang, Z. Persistent inflammation-induced up-regulation of brain-derived neurotrophic factor (BDNF) promotes synaptic delivery of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA1 subunits in descending pain modulatory circuits. J. Biol. Chem. 2014, 289, 22196–22204. [Google Scholar] [CrossRef] [PubMed]
  127. 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. [Google Scholar] [CrossRef]
  128. Jasim, H.; Ghafouri, B.; Gerdle, B.; Hedenberg-Magnusson, B.; Ernberg, M. Altered levels of salivary and plasma pain related markers in temporomandibular disorders. J. Headache Pain 2020, 21, 105. [Google Scholar] [CrossRef]
  129. Deitos, A.; Dussan-Sarria, J.A.; Souza, A.; Medeiros, L.; Tarrago Mda, G.; Sehn, F.; Chassot, M.; Zanette, S.; Schwertner, A.; Fregni, F.; et al. Clinical Value of Serum Neuroplasticity Mediators in Identifying the Central Sensitivity Syndrome in Patients With Chronic Pain With and Without Structural Pathology. Clin. J. Pain 2015, 31, 959–967. [Google Scholar] [CrossRef]
  130. Ranzolin, A.; Duarte, A.L.; Bredemeier, M.; da Costa Neto, C.A.; Ascoli, B.M.; Wollenhaupt-Aguiar, B.; Kapczinski, F.; Xavier, R.M. Evaluation of cytokines, oxidative stress markers and brain-derived neurotrophic factor in patients with fibromyalgia—A controlled cross-sectional study. Cytokine 2016, 84, 25–28. [Google Scholar] [CrossRef]
  131. Iannuccelli, C.; Lucchino, B.; Gioia, C.; Dolcini, G.; Rabasco, J.; Venditto, T.; Ioppolo, F.; Santilli, V.; Conti, F.; Di Franco, M. Gender influence on clinical manifestations, depressive symptoms and brain-derived neurotrophic factor (BDNF) serum levels in patients affected by fibromyalgia. Clin. Rheumatol. 2022, 41, 2171–2178. [Google Scholar] [CrossRef] [PubMed]
  132. 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. [Google Scholar] [CrossRef] [PubMed]
  133. 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. [Google Scholar] [CrossRef] [PubMed]
  134. 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. [Google Scholar] [CrossRef] [PubMed]
  135. 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. [Google Scholar] [CrossRef] [PubMed]
  136. 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. [Google Scholar] [CrossRef]
  137. 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. [Google Scholar] [CrossRef]
  138. 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. [Google Scholar] [CrossRef]
  139. Verhagen, M.; van der Meij, A.; van Deurzen, P.A.; Janzing, J.G.; Arias-Vasquez, A.; Buitelaar, J.K.; Franke, B. Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder: Effects of gender and ethnicity. Mol. Psychiatry 2010, 15, 260–271. [Google Scholar] [CrossRef]
  140. Goto, T.; Von Ah, D.; Li, X.; Xiang, L.; Kwiat, C.; Nguyen, C.; Hsiao, C.P.; Saligan, L.N. Brain-Derived Neurotrophic Factor rs6265 polymorphism is associated with severe cancer-related fatigue and neuropathic pain in female cancer survivors. J. Cancer Surviv. 2023. [Google Scholar] [CrossRef]
  141. Lamy, J.C.; Boakye, M. BDNF Val66Met polymorphism alters spinal DC stimulation-induced plasticity in humans. J. Neurophysiol. 2013, 110, 109–116. [Google Scholar] [CrossRef] [PubMed]
  142. 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. [Google Scholar] [CrossRef] [PubMed]
  143. Dincheva, I.; Glatt, C.E.; Lee, F.S. Impact of the BDNF Val66Met polymorphism on cognition: Implications for behavioral genetics. Neuroscientist 2012, 18, 439–451. [Google Scholar] [CrossRef] [PubMed]
  144. Volz, M.S.; Suarez-Contreras, V.; Portilla, A.L.; Fregni, F. Mental imagery-induced attention modulates pain perception and cortical excitability. BMC Neurosci. 2015, 16, 15. [Google Scholar] [CrossRef] [PubMed]
  145. 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. [Google Scholar] [CrossRef] [PubMed]
  146. Harrison, R.A.; Rao, V.; Kesler, S.R. The association of genetic polymorphisms with neuroconnectivity in breast cancer patients. Sci. Rep. 2021, 11, 6169. [Google Scholar] [CrossRef]
  147. Chang, W.J.; Jenkins, L.C.; Humburg, P.; Schabrun, S.M. Human assumed central sensitization in people with acute non-specific low back pain: A cross-sectional study of the association with brain-derived neurotrophic factor, clinical, psychological and demographic factors. Eur. J. Pain 2023, 27, 530–545. [Google Scholar] [CrossRef]
  148. Jenkins, L.C.; Chang, W.J.; Buscemi, V.; Liston, M.; Humburg, P.; Nicholas, M.; Graven-Nielsen, T.; Hodges, P.W.; McAuley, J.H.; Schabrun, S.M. Cortical function and sensorimotor plasticity are prognostic factors associated with future low back pain after an acute episode: The Understanding persistent Pain Where it ResiDes prospective cohort study. Pain 2023, 164, 14–26. [Google Scholar] [CrossRef]
  149. Jenkins, L.C.; Chang, W.J.; Buscemi, V.; Liston, M.; Skippen, P.; Cashin, A.G.; McAuley, J.H.; Schabrun, S.M. Low Somatosensory Cortex Excitability in the Acute Stage of Low Back Pain Causes Chronic Pain. J. Pain 2022, 23, 289–304. [Google Scholar] [CrossRef]
  150. Yamada, A.S.; Antunes, F.T.T.; Ferraz, C.; de Souza, A.H.; Simon, D. The genetic influence of the brain-derived neurotrophic factor Val66Met polymorphism in chronic low back pain. Adv. Rheumatol. 2021, 61, 24. [Google Scholar] [CrossRef]
  151. Reddy, S.Y.; Rasmussen, N.A.; Fourie, N.H.; Berger, R.S.; Martino, A.C.; Gill, J.; Longchamps, R.; Wang, X.M.; Heitkemper, M.M.; Henderson, W.A. Sleep quality, BDNF genotype and gene expression in individuals with chronic abdominal pain. BMC Med. Genom. 2014, 7, 61. [Google Scholar] [CrossRef] [PubMed]
  152. Kerr, J.I.; Burri, A. Genetic and epigenetic epidemiology of chronic widespread pain. J. Pain Res. 2017, 10, 2021–2029. [Google Scholar] [CrossRef] [PubMed]
  153. 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. [Google Scholar] [CrossRef] [PubMed]
  154. Crow, M.; Denk, F.; McMahon, S.B. Genes and epigenetic processes as prospective pain targets. Genome Med. 2013, 5, 12. [Google Scholar] [CrossRef] [PubMed]
  155. Mauceri, D. Role of Epigenetic Mechanisms in Chronic Pain. Cells 2022, 11, 2613. [Google Scholar] [CrossRef] [PubMed]
  156. 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. [Google Scholar] [CrossRef] [PubMed]
  157. 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. [Google Scholar] [CrossRef] [PubMed]
  158. 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. [Google Scholar] [CrossRef]
  159. 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. [Google Scholar] [CrossRef]
  160. Sun, W.; Zhang, L.; Li, R. Overexpression of miR-206 ameliorates chronic constriction injury-induced neuropathic pain in rats via the MEK/ERK pathway by targeting brain-derived neurotrophic factor. Neurosci. Lett. 2017, 646, 68–74. [Google Scholar] [CrossRef]
  161. Tu, W.; Yue, J.; Li, X.; Wu, Q.; Yang, G.; Li, S.; Sun, Q.; Jiang, S. Electroacupuncture Alleviates Neuropathic Pain through Regulating miR-206-3p Targeting BDNF after CCI. Neural Plast. 2022, 2022, 1489841. [Google Scholar] [CrossRef] [PubMed]
  162. Erickson, K.I.; Voss, M.W.; Prakash, R.S.; Basak, C.; Szabo, A.; Chaddock, L.; Kim, J.S.; Heo, S.; Alves, H.; White, S.M.; et al. Exercise training increases size of hippocampus and improves memory. Proc. Natl. Acad. Sci. USA 2011, 108, 3017–3022. [Google Scholar] [CrossRef] [PubMed]
  163. Smith, M.A.; Makino, S.; Kvetnansky, R.; Post, R.M. Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J. Neurosci. 1995, 15, 1768–1777. [Google Scholar] [CrossRef] [PubMed]
  164. Havekes, R.; Vecsey, C.G.; Abel, T. The impact of sleep deprivation on neuronal and glial signaling pathways important for memory and synaptic plasticity. Cell Signal 2012, 24, 1251–1260. [Google Scholar] [CrossRef]
  165. Berger, S.L. The complex language of chromatin regulation during transcription. Nature 2007, 447, 407–412. [Google Scholar] [CrossRef]
  166. Descalzi, G.; Ikegami, D.; Ushijima, T.; Nestler, E.J.; Zachariou, V.; Narita, M. Epigenetic mechanisms of chronic pain. Trends Neurosci. 2015, 38, 237–246. [Google Scholar] [CrossRef]
  167. 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. [Google Scholar] [CrossRef]
  168. 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. [Google Scholar] [CrossRef]
  169. 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. [Google Scholar] [CrossRef]
  170. 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. [Google Scholar] [CrossRef]
  171. 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. [Google Scholar] [CrossRef] [PubMed]
  172. 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. [Google Scholar] [CrossRef] [PubMed]
  173. 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. [Google Scholar] [CrossRef] [PubMed]
  174. 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. [Google Scholar] [CrossRef] [PubMed]
  175. 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. [Google Scholar] [CrossRef] [PubMed]
  176. 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. [Google Scholar] [CrossRef] [PubMed]
  177. 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. [Google Scholar] [CrossRef]
  178. Suchting, R.; Teixeira, A.L.; Ahn, B.; Colpo, G.D.; Park, J.; Ahn, H. Changes in Brain-derived Neurotrophic Factor From Active and Sham Transcranial Direct Current Stimulation in Older Adults With Knee Osteoarthritis. Clin. J. Pain 2021, 37, 898–903. [Google Scholar] [CrossRef]
  179. da Silva Moreira, S.F.; Medeiros, L.F.; de Souza, A.; de Oliveira, C.; Scarabelot, V.L.; Fregni, F.; Caumo, W.; Torres, I.L. Transcranial direct current stimulation (tDCS) neuromodulatory effects on mechanical hyperalgesia and cortical BDNF levels in ovariectomized rats. Life Sci. 2016, 145, 233–239. [Google Scholar] [CrossRef]
  180. 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. [Google Scholar] [CrossRef]
  181. 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. [Google Scholar] [CrossRef] [PubMed]
  182. 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. [Google Scholar] [CrossRef] [PubMed]
  183. 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. [Google Scholar] [CrossRef] [PubMed]
  184. Pedersen, B.K. Physical activity and muscle-brain crosstalk. Nat. Rev. Endocrinol. 2019, 15, 383–392. [Google Scholar] [CrossRef] [PubMed]
  185. 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. [Google Scholar] [CrossRef] [PubMed]
  186. 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. [Google Scholar] [CrossRef] [PubMed]
  187. Knaepen, K.; Goekint, M.; Heyman, E.M.; Meeusen, R. Neuroplasticity-exercise-induced response of peripheral brain-derived neurotrophic factor: A systematic review of experimental studies in human subjects. Sports Med. 2010, 40, 765–801. [Google Scholar] [CrossRef]
  188. Senba, E.; Kami, K. A new aspect of chronic pain as a lifestyle-related disease. Neurobiol. Pain 2017, 1, 6–15. [Google Scholar] [CrossRef]
  189. Polli, A.; Ickmans, K.; Godderis, L.; Nijs, J. When Environment Meets Genetics: A Clinical Review of the Epigenetics of Pain, Psychological Factors, and Physical Activity. Arch. Phys. Med. Rehabil. 2019, 100, 1153–1161. [Google Scholar] [CrossRef]
  190. Boulle, F.; Kenis, G.; Cazorla, M.; Hamon, M.; Steinbusch, H.W.; Lanfumey, L.; van den Hove, D.L. TrkB inhibition as a therapeutic target for CNS-related disorders. Prog. Neurobiol. 2012, 98, 197–206. [Google Scholar] [CrossRef]
  191. Chen, D.Y.; Bambah-Mukku, D.; Pollonini, G.; Alberini, C.M. Glucocorticoid receptors recruit the CaMKIIalpha-BDNF-CREB pathways to mediate memory consolidation. Nat. Neurosci. 2012, 15, 1707–1714. [Google Scholar] [CrossRef] [PubMed]
  192. Yajima, Y.; Narita, M.; Usui, A.; Kaneko, C.; Miyatake, M.; Narita, M.; Yamaguchi, T.; Tamaki, H.; Wachi, H.; Seyama, Y.; et al. Direct evidence for the involvement of brain-derived neurotrophic factor in the development of a neuropathic pain-like state in mice. J. Neurochem. 2005, 93, 584–594. [Google Scholar] [CrossRef] [PubMed]
  193. Schulte-Herbruggen, O.; Nassenstein, C.; Lommatzsch, M.; Quarcoo, D.; Renz, H.; Braun, A. Tumor necrosis factor-alpha and interleukin-6 regulate secretion of brain-derived neurotrophic factor in human monocytes. J. Neuroimmunol. 2005, 160, 204–209. [Google Scholar] [CrossRef] [PubMed]
  194. Poutoglidou, F.; Pourzitaki, C.; Manthou, M.E.; Malliou, F.; Saitis, A.; Tsimoulas, I.; Panagiotopoulos, S.; Kouvelas, D. Effects of long-term infliximab and tocilizumab treatment on anxiety-like behavior and cognitive function in naive rats. Pharmacol. Rep. 2022, 74, 84–95. [Google Scholar] [CrossRef] [PubMed]
  195. 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. [Google Scholar] [CrossRef] [PubMed]
  196. 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. [Google Scholar] [CrossRef] [PubMed]
  197. 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. [Google Scholar] [CrossRef]
  198. 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. [Google Scholar] [CrossRef]
  199. Thakkar, B.; Acevedo, E.O. BDNF as a biomarker for neuropathic pain: Consideration of mechanisms of action and associated measurement challenges. Brain Behav. 2023, 13, e2903. [Google Scholar] [CrossRef]
  200. Zorina-Lichtenwalter, K.; Meloto, C.B.; Khoury, S.; Diatchenko, L. Genetic predictors of human chronic pain conditions. Neuroscience 2016, 338, 36–62. [Google Scholar] [CrossRef]
Biomolecules 14 00071 g001
Figure 1. The role of BDNF in central sensitization and neuroinflammation.
Figure 1. The role of BDNF in central sensitization and neuroinflammation.
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Figure 2. The epigenetic regulation of BDNF expression.
Figure 2. The epigenetic regulation of BDNF expression.
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Table 3. DNA Methylation Changes in BDNF gene in patients with chronic pain.
Table 3. DNA Methylation Changes in BDNF gene in patients with chronic pain.
ReferenceStudy PopulationStudy
Design		Epigenetic
Assessment		TissueAssayMain Results
Polli et al., 2020 [127]Chronic fatigue syndrome and comorbid fibromyalgia (n = 28)
Healthy controls (n = 26)		Cross-sectionalDNA methylation (BDNF gene-specific)BloodPCR amplification, pyrosequencingCompared to controls, serum BNDF was higher in patients with CFS/FM (mean difference of 3.31 ng/mL; p = 0.001), whereas BDNF DNA methylation in exon 9 was lower (mean difference of −2.16%; p = 0.007).
Lower methylation in the same region predicted higher BDNF levels (p = 0.009), which in turn predicted participants’ symptoms (p = 0.001) and widespread hyperalgesia (p = 0.044).
Paoloni-Giacobino et al., 2020 [158]Chronic musculoskeletal pain (n = 58)
Healthy controls (n = 18)		Cross-sectionalDNA methylation (BDNF gene-specific)BloodPCR amplification, pyrosequencingThe methylation values of BDNF were significantly (p< 0.005) increased 1.9-fold in patients with CMS as compared with the healthy controls.
A high level of biopsychosocial complexity was associated with lower average CpG methylation values of BDNF (p = 0.02) in patients with CMS, and may therefore increase the level of BDNF.
The upregulation of BDNF is associated with higher levels of biopsychosocial complexity.
Menzies et al., 2013 [159] Fibromyalgia (n = 10)
Healthy controls (n = 8)		Cross-sectionalDNA methylation (genome-wide)Blood450 K human methylation assayAuthors found 69 differently methylated positions, in 47 different genes, i.e., AXL, HDAC4, BDNF, PRKCA, RTN1, PRKG1, SOD3. There is a significant difference in the methylation pattern of the BDNF gene between patients with FM and controls.
BDNF, brain-derived neurotrophic factor; PCR, polymerase chain reaction; CMS, patients with chronic musculoskeletal pain; CFS, chronic fatigue syndrome; FM, fibromyalgia.
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Xiong, H.-Y.; Hendrix, J.; Schabrun, S.; Wyns, A.; Campenhout, J.V.; Nijs, J.; Polli, A. The Role of the Brain-Derived Neurotrophic Factor in Chronic Pain: Links to Central Sensitization and Neuroinflammation. Biomolecules 2024, 14, 71. https://doi.org/10.3390/biom14010071

AMA Style

Xiong H-Y, Hendrix J, Schabrun S, Wyns A, Campenhout JV, Nijs J, Polli A. The Role of the Brain-Derived Neurotrophic Factor in Chronic Pain: Links to Central Sensitization and Neuroinflammation. Biomolecules. 2024; 14(1):71. https://doi.org/10.3390/biom14010071

Chicago/Turabian Style

Xiong, Huan-Yu, Jolien Hendrix, Siobhan Schabrun, Arne Wyns, Jente Van Campenhout, Jo Nijs, and Andrea Polli. 2024. "The Role of the Brain-Derived Neurotrophic Factor in Chronic Pain: Links to Central Sensitization and Neuroinflammation" Biomolecules 14, no. 1: 71. https://doi.org/10.3390/biom14010071

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