Next Article in Journal
Peripheral Ion Channel Gene Screening in Painful- and Painless-Diabetic Neuropathy
Previous Article in Journal
In Vitro Wound Healing Properties of Novel Acidic Treatment Regimen in Enhancing Metabolic Activity and Migration of Skin Cells
Previous Article in Special Issue
COVID-19: Immunohistochemical Analysis of TGF-β Signaling Pathways in Pulmonary Fibrosis
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 23
Issue 13
10.3390/ijms23137191
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Neuroimmune Mechanisms Underlying Neuropathic Pain: The Potential Role of TNF-α-Necroptosis Pathway

by
Yi-Wen Duan
1,†,
Shao-Xia Chen
2,†,
Qiao-Yun Li
1 and
Ying Zang
1,*
1
Pain Research Center and Department of Physiology, Zhongshan Medical School, Sun Yat-sen University, 74 Zhongshan Road. 2, Guangzhou 510080, China
2
Department of Anesthesiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this study.
Int. J. Mol. Sci. 2022, 23(13), 7191; https://doi.org/10.3390/ijms23137191
Submission received: 9 May 2022 / Revised: 24 June 2022 / Accepted: 27 June 2022 / Published: 28 June 2022
(This article belongs to the Special Issue Cytokine Release Syndrome: From Cell Metabolism to Organ Dysfunction)
Browse Figures
Review Reports Versions Notes

Abstract

:
The neuroimmune mechanism underlying neuropathic pain has been extensively studied. Tumor necrosis factor-alpha (TNF-α), a key pro-inflammatory cytokine that drives cytokine storm and stimulates a cascade of other cytokines in pain-related pathways, induces and modulates neuropathic pain by facilitating peripheral (primary afferents) and central (spinal cord) sensitization. Functionally, TNF-α controls the balance between cell survival and death by inducing an inflammatory response and two programmed cell death mechanisms (apoptosis and necroptosis). Necroptosis, a novel form of programmed cell death, is receiving increasing attraction and may trigger neuroinflammation to promote neuropathic pain. Chronic pain is often accompanied by adverse pain-associated emotional reactions and cognitive disorders. Overproduction of TNF-α in supraspinal structures such as the anterior cingulate cortex (ACC) and hippocampus plays an important role in pain-associated emotional disorders and memory deficits and also participates in the modulation of pain transduction. At present, studies reporting on the role of the TNF-α–necroptosis pathway in pain-related disorders are lacking. This review indicates the important research prospects of this pathway in pain modulation based on its role in anxiety, depression and memory deficits associated with other neurodegenerative diseases. In addition, we have summarized studies related to the underlying mechanisms of neuropathic pain mediated by TNF-α and discussed the role of the TNF-α–necroptosis pathway in detail, which may represent an avenue for future therapeutic intervention.

1. Introduction

Massive unregulated release of pro-inflammatory cytokines (cytokine storm) such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) due to infection, nerve injury or immunotherapy causes organ damage and unbearable pain [1]. Neuropathic pain, caused by inflammatory cytokines, is a prominent symptom of cytokine storm and is characterized by a burning or electrical-like sensation, an unpleasant somatosensory experience leading to hyperalgesia (increased sensitivity to noxious stimuli), allodynia (pain evoked by normally innocuous stimuli) and spontaneous pain [2,3,4,5,6,7,8,9,10,11]. It is mainly secondary to central or peripheral nerve damage, cancer, diabetes, infection, stroke or immune and inflammatory disorders [12,13,14,15]. Because neuropathic pain is complex, impairs the quality of life of patients, increases the economic burden of patients [16,17,18,19] and lacks effective therapies, it is a clinical dilemma that warrants immediate attention. Over the past 30 years, various experimental and animal models have been used to examine the underlying mechanisms of neuropathic pain; among which, neuroimmune mechanisms have received increasing attention [20,21,22,23,24,25,26,27,28]. Although neuropathic pain is a sensory disorder, in the lumbar 5 ventral root transection (L5-VRT) model, motor fiber injury but not sensory fiber injury is crucial to the onset and development of neuropathic pain because it initiates neuroinflammatory responses such as the elevation of pro-inflammatory cytokine levels in pain-related pathways, thus facilitating peripheral and central sensitization [21,22,23,24,29,30,31,32,33,34]. Intra-sciatic injection or peri-sciatic administration of exogenous tumor necrosis factor-alpha (TNF-α) without any nerve injury reproduces pain hypersensitivity similar to that of neuropathic pain in humans [35,36], indicating that neuroinflammatory responses, instead of nerve injury, are necessary and sufficient for inducing neuropathic pain.
Microglia in the healthy brain continuously palpate the surrounding tissue for subtle disturbances [37] and can rapidly respond to tissue injury by altering morphological characteristics, proliferating and expressing a wide variety of inflammatory cytokines and chemokines [38]. Multiple studies have indicated that the local microenvironment plays an important role in regulating the microglial phenotype [39,40,41,42,43,44]. Microglial activation can be initiated by injured neurons [45,46,47,48], which contributes to central nervous system (CNS) pathology, such as in models of neuropathic pain [22,46,48,49,50,51,52]. A recent study showed that impaired death (necroptosis) and/or repopulation of microglia underpin their dysregulated activation in neurological diseases [53]; in addition, necroptosis can be triggered by many death receptors, including Fas, TRAIL and TNF receptors, mainly through the signalling pathway induced via the binding of TNF-α to TNF receptor 1 (TNFR1) [54]. Therefore, the TNF-α/TNFR–necroptosis pathway, a biochemical pathway causing programmed neurodegeneration and/or microglia death, may be responsible for or contribute to neuropathic pain. This review focuses on the peripheral and central mechanisms of neuropathic pain mediated by TNF-α, provides data regarding available potential therapeutic targets and suggests future research directions related to the TNF-α/TNFR–necroptosis pathway for neuropathic pain.

2. Inflammatory Response, Apoptosis and Necroptosis Induced by TNF-α

TNF-α is important for mammalian immunity and cellular homeostasis. The role of TNF-α as a master regulator in balancing cell survival and death has been extensively studied in various cell types and tissues. As shown in Figure 1, TNF-α induces an inflammatory response and two programmed cell death mechanisms, namely, apoptosis and necroptosis, based on different pathological conditions [54,55,56,57,58]. Receptor interacting protein kinase 1 (RIPK1) and TNF receptor-associated death domain (TRADD) regulate TNF-dependent signalling, which controls the balance between cell death and survival [59].

2.1. Cell Survival and Inflammatory Response

When TNF-α binds to TNFR1 on the membrane surface, the conformation of TNFR1 changes, and TNFR1 complex I is rapidly formed via the recruitment of various proteins, including TRADD, RIPK1, TNF receptor-associated factor 2 (TRAF2) and cellular inhibitor of apoptosis protein 1 and 2 (cIAP1/2). TRADD is very important for the recruitment of TRAF2 and ubiquitination of RIPK1 and complex I. The TGF-activated kinase 1 (TAK1) binding protein (TAB) complex and IκB kinase (IKK) complex consisting of IKK1 can prevent cell death, whereas cIAP1/2 can prevent TNFR1-mediatednecroptosis and promote ubiquitination of RIPK1 [60,61]. Ubiquitination of RIPK1 activates the NF-κB signalling pathway through TAK and IKK complexes, promotes cell survival and induces an inflammatory response [62].

2.2. Apoptosis

Deubiquitination of RIPK1 results in the formation of either complex IIa or complex IIb. If caspase-8 is present in cells, TNFR1 complex I recruits TRADD and caspase-8 to form complex IIa (composed of TRADD, FADD and caspase-8), activating a caspase cascade and leading to RIPK1-independent apoptosis (RIA). When receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) protein are fully expressed and caspase-8 is present, ubiquitination of RIPK1 is inhibited, and it interacts with RIPK3 to form complex IIb (mainly composed of FADD, caspase-8, RIPK1 and RIPK3), which activates caspase-8 and triggers RIPK1-dependent apoptosis (RDA) [63,64].

2.3. Necroptosis

Stimulation of the Fas/TNFR family can not only trigger a canonical ‘extrinsic’ apoptotic pathway but also activate necroptosis inhibited by necrostatin-1 (Nec-1), a specific and potent small-molecule substance, in the absence of intracellular apoptotic signalling [65]. When caspase-8 is inactive or inhibited, necroptosis is initiated via complex IIb. RIPK1 recruits RIPK3 and induces auto- and trans-phosphorylation, with consequent oligomerisation of the phosphorylated RIPK3. After phosphorylation, RIPK1 and RIPK3 form a necrosome (a multiprotein complex resembling amyloids) with MLKL. RIPK3 recruits MLKL and phosphorylates it. Subsequently, MLKL oligomerises and migrates to the cell membrane from the cytoplasm, which results in membrane permeabilization owing to the binding of MLKL to phosphatidylinositol lipids and cardiolipin, thus leading to cell death [66,67].

3. Role of TNF-α and Its Mechanism Underlying Neuropathic Pain

TNF-α, which primarily activates a cascade of other cytokines [68], is upregulated in both the peripheral nervous system [21,69,70,71] and CNS, including the hippocampus [72,73], locus coeruleus [72,74], medial prefrontal cortex (mPFC) [75], anterior cingulate cortex(ACC) [20] and spinal cord [21] in animal pain models, thereby mediating the initiation and maintenance of neuropathic pain (Figure 2) [66,76,77,78].

3.1. TNF-α Regulates Voltage-Gated Sodium Channels in the Peripheral Nervous System

Studies have shown that TNF-α facilitates heat-induced CGRP release from nociceptor terminals in the skin [79] and sensitizes peripheral Aβ- and C-fibers [80,81,82,83]. This sensitization of peripheral primary afferents by TNF-α results from the abnormal expression of voltage-gated sodium channels (VGSCs) in the dorsal root ganglia (DRG) [84,85,86]. Selective injury of motor fibers via L5-VRT upregulates the expression of TNF-α [21], tetrodotoxin-sensitive (TTX-S) Nav1.3 and tetrodotoxin-resistant (TTX-R) Nav1.8 [23] and increases the current density of TTX-S and TTX-R channels in DRG [23,87]. The increase in the expression of the above mentioned VGSCs and sodium currents is reported to be significantly lower in TNFR1-knockout mice than in wild-type mice [23,87]. Furthermore, peri-sciatic exogenous TNF-α, which leads to lasting mechanical allodynia [71], upregulates Nav1.3 and Nav1.8 in DRG in vivo. In addition, TNF-α-induced Nav1.3 and Nav1.8 can be formed in cultured adult rat DRG in a dose-dependent manner [23]. Nuclear factor-kappaB (NF-κB) and p38 mitogen-activated protein kinase (p38 MAPK) pathways mediate the abnormal expression of VGSCs or sodium currents following nerve injury [25,87].
Nav1.6 (SCN8A), another major TTX-S VGSC in the mammalian nervous system, regulates neuronal activity at the axon initial segment [88], relays excitatory persistent and resurgent currents in DRG [89] and is involved in the production and maintenance of pathological neuronal excitability in the peripheral nerves [90,91]. In DRG, spontaneously active bursting cells express high levels of Nav1.6 and knockdown of Nav1.6 completely blocks the abnormal spontaneous activity and pain behaviors [84,90,91,92,93]. TNF-α can directly regulate the expression and function of Nav1.6 by epigenetically upregulating Nav1.6 expression via the signal transducer and activator of transcription-3 (STAT3) pathway, which promotes the trafficking of Nav1.6 to the membrane of neurons in DRG, an essential step in mediating neuronal excitability and repetitive firing, thus contributing to neuropathic pain [84,94].
TTX-S Nav1.7 (SCN9A) has been intensively studied in the sensory system. In humans, the loss of function of Nav1.7 leads to a complete inability to sense pain [95,96], and mutations inNav1.7 lead to the functional absence of nociceptors [97]. However, the gain of function of Nav1.7 results in paroxysmal extreme pain disorder [98]. In rodents, deletion or blockage of Nav1.7 in mouse DRG attenuates nerve injury-, inflammation-, burn injury- and paclitaxel (a chemotherapeutic drug)-induced chronic pain [99,100,101,102,103]. Previous studies have shown that TNF-α/NF-κB signalling induces hypersensitivity in DRG via nuclear transcription [104]. In addition, a recent study showed that NF-κB p-p65 non-transcriptionally gates Nav1.7 channels in the membrane of neurons in rat DRG, and TNF-α contributes to the protein–protein interaction between p-p65 and Nav1.7 within several minutes [105], revealing the possible mechanism underlying the rapid regulation of sodium currents by TNF-α [87].
In addition to regulating VGSCs, TNF-α can increase the conductance of transient receptor potential ankyrin 1 (TRPA1) [106], transient receptor potential vanilloid 1(TRPV1) [107,108], voltage-gated calcium channel subunit CaV3.2 [86] and membrane K+ ions [109]. In response to nerve injury and inflammation, overexpression of TNF-α in the peripheral nervous system sensitises primary afferents by enhancing the cation channels to induce neuropathic pain.

3.2. TNF-α Induces Spinal Neuronal Excitation and Inhibition Imbalance Andneuroinflammation

In the spinal cord, TNF-α enhances excitatory synaptic transmission and increases AMPA- and NMDA-evoked excitatory postsynaptic currents (EPSCs) to induce pain hypersensitivity [110]. After nerve injury, the upregulation of TNF-α may activate NF-κB, p38 MAPK and JNK via TNFR1 on neurons and glial cells to induce long-term potentiation (LTP) of C-fibre-evoked field potentials in the spinal dorsal horn [111]. In addition, TNF-α can reduce inhibitory synaptic transmission, indicating that disinhibition of synaptic transmission is mediated by TNF-α/TNFR1 followed by the activation of the p38 MAPK pathway in GABAergic neurons of the spinal cord [78]. In addition to the neuronal excitation and inhibition imbalance, TNF-α-induced neuroinflammation and spinal microglial activation contribute to neuropathic pain by initiating the release of other proinflammatory cytokines and promoting crosstalk between neurons and glial cells to affect synaptic signalling and pain transmission [21,22,112]. In the spinal cord, activation of TNF-α after spinal cord injury and noxious stimulation promotes NF-κB, extracellular signal-regulated kinase (ERK), JNK and caspase-8 pathways, thereby initiating inflammatory and apoptotic processes to affect the development and maintenance of neuropathic pain [113]. Furthermore, microglia-derived TNF-α elevates the expression of cyclooxygenase 2 and prostaglandin I2 (PGI2) synthase in spinal endothelial cells, which promotes neuropathic pain via the neuronal PGI2 receptor [114], suggesting that the glial–endothelial cell interaction of the neurovascular unit via transient TNF-α is responsible for the generation of neuropathic pain.

3.3. Supraspinal TNF-α Mediates Neuropathic Pain, Pain-Associated Aversion, Anxiety, Depression and Memory Deficits

Changes in higher-order functions, such as learning and memory disorders, anxiety or depression, are critical components of pain phenotypes, especially in a chronic pain state [115,116,117,118]. TNF-α plays a key role in supraspinal modulation of pain transduction; for example, intracerebroventricular (ICV) injection of TNF-α induces hyperalgesia [119,120]. In addition, blocking TNF-α in the brain reduces neuropathic pain, pain-associated aversion and memory deficits [20,117,121]. Glial cells are considered a major source of cytokines and chemokines in the brain [122], and the activation of microglia in ACC, hippocampus, prefrontal cortex and other brain regions associated with pain information processing contributes to pain aversion [123], memory deficits [124], anxiety and depression [124] and may be associated with overexpression of TNF-α [20,125]. Reciprocal activation between neurons and microglia facilitates pain transmission [75,121,126].
At the molecular level, supraspinal TNF-α modulates excitatory and inhibitory synaptic transmission in different ways [127]. Overproduction of TNF-α enhances the phosphorylation of NMDA receptor subunit NR1 in the rostral ventromedial medulla (RVM), contributing to descending pain facilitation [121]. In oxaliplatin-induced pain models, TNF-α is upregulated in the dorsolateral region of the midbrain periaqueductal gray, which is accompanied by an impaired GABAergic descending inhibitory system [128]. Activation of the NF-kB, ERK, p38 MAPK and JNK pathways induced by supraspinal TNF-α is responsible for SNI-induced neuropathic pain [129]. Furthermore, activation of TNF-α/TNFR1 and microglia following nerve injury mediates opposite structural synaptic alterations in spinal (induction of LTP) [111,112] and hippocampal (inhibition of LTP) neurons [130,131,132,133,134,135], which may be used to explain hyperalgesia/allodynia and pain-associated memory disorders, respectively.

4. TNF-α/TNFR1-Necroptosis Pathway in Neuropathic Pain

In addition to TNF-α-mediated neuroinflammation and excitotoxicity [20], apoptosis induced by TNF-α/TNFR1 [64,136,137,138] also promotes peripheral neuropathic pain [139,140]. Necroptosis, a novel form of TNF-α-mediated cell death, has attracted increasing attention in the past decade. As shown in Figure 3A, the number of articles published worldwide shows a steady upward trend, with the research explosion point of necroptosis in the field of neuroscience beginning in 2014.

4.1. Necroptosis and Bibliometric Analysis

Necroptosis is characterised by necrotic cell death and autophagy activation [65,146]. In 1988, Laser et al. found that cell necrosis can be regulated and occurs actively [141]. Subsequently, some studies reported a death mechanism that lacked apoptotic signalling; however, the morphological features of cell death were similar to those of necrosis [142]. After a few years, Chan et al. reported receptor-interacting protein (RIP)-dependent programmed necrosis [143]. In addition, Degterev et al. found that Nec-1 and related molecules can regulate the aforementioned form of cell death and termed it necroptosis [65,144]. Finally, necroptosis was officially named in 2018 [145]. The developmental process is shown in Figure 3B. Necroptosis results in morphological characteristics similar to those of necrosis and activates autophagy but appears to be tightly regulated [65,147,148].
The literature published on necroptosis in the field of neuroscience from 2012 to 2021 was quantitatively and qualitatively analyzed using the Bibliometrix R Package and VOSviewer software [149,150], and the top 10 articles with the highest co-citation rate and the top 10 most cited articles are listed in Table 1, Table 2 and Table 3, respectively. Most publications in Table 1 belong to Q1 in the Journal Citation Reports (JCR) division, reflecting the necessity of in-depth research on necroptosis to a certain extent. Research into necroptosis in the field of neuroscience has gradually deepened, with studies focusing on various aspects from molecular mechanisms to the pathogenesis of central diseases (Table 2 and Table 3).
Keyword co-occurrence analysis performed using VOSviewer revealed four categories of keywords related to necroptosis, which are shown in red, blue, green and yellow in Figure 4. The red clusters are largest, and ‘necroptosis’ constitutes the largest node. In addition, the occurrence of terms such as ‘inflammation’, ‘oxidative stress’, ‘activation’ and ‘neurodegeneration’ suggests that necroptosis activation is closely related to neuroinflammation and neurodegeneration.

4.2. TNF-α/TNFR1–Necroptosis Pathway Contributes to Neurological Diseases

As mentioned above (Figure 1), necroptosis is activated by ligands of death receptors such as TNF-α under caspase-deficient conditions. RIPK3 and MLKL are important for necroptosis activation [58,152,153,154,155,158,165,166]. TNF-α/TNFR1-induced necroptosis occurs in several neurodegenerative diseases of the CNS, such as multiple sclerosis (MS), Parkinson’s disease and Alzheimer’s disease [156,167,168,169,170]. After an ischaemic stroke, perivascular microglia-induced endothelial necroptosis leading to disruption of the blood–brain barrier requires TNF-α to act on its receptor TNFR1 [57]. Furthermore, chronic pain induced by SNI sensitizes the heart to myocardial ischaemia–reperfusion injury, and myocardial necroptosis plays an important role in this pathophysiological process, with an increase in TNF-α levels following by a robust interaction between RIP1/RIP3 and RIP3-induced phosphor-MLKL/CaMKII signalling [171].

4.3. Role of Necroptosis in Chronic Pain

Necroptosis, a mode of programmed cell death similar to necrosis and conventional apoptosis, is usually accompanied by plasma membrane rupture, organelle swelling and inflammatory cell infiltration [61,147]. RIP3, the core regulatory protein of necroptosis, activates inflammasome 3 and caspase-1, thus promoting the secretion of the pro-inflammatory cytokines TNF-α and IL-1β [172]. Therefore, it may be a trigger for neuroinflammation [55,61,173,174,175] and promotes neuropathic pain via activated microglia [176]. A study on rat models of paclitaxel (PTX)-induced hyperalgesia reported that the necroptosis-related proteins RIP3/MLKL regulated neuronal necroptosis and increased the levels of pro-inflammatory cytokines in DRG [177]. In another study on rat models, peripheral nerve injury induced by CCI or SNI increased the expression of TNF-α, RIP1 and/or RIP3 [176,178] in the spinal cord, whereas Nec-1, an effective inhibitor of RIP1 and RIP-mediated necroptosis [65,159], significantly reduced the levels of spinal pro-inflammatory cytokines and RIP1/RIP3 and alleviated neuropathic hyperalgesia and allodynia [176,178].
Neuroinflammation owing to abnormally elevated TNF-α levels in the primary sensory afferent, spinal cord and ACC following peripheral nerve injury contributes to neuropathic pain [20,21,71]. Peri-sciatic administration of exogenous TNF-α without any nerve injury induces mechanical allodynia by activating the NF-kappaB pathway via an autocrine mechanism [71]. The TNF-α/TNFR1–necroptosis pathway may be a new and important target for research into chronic pain (Figure 2).

4.4. TNF-α/Necroptosis in Pain-Associated Anxiety and Depression

Chronic pain is often accompanied by adverse pain-associated emotional reactions such as anxiety and depression [179,180]. Several studies have been reported on emotional problems and chronic pain [181,182,183]. An increase in the levels of proinflammatory cytokines [184,185] and a decrease in the levels of neurotrophins [186,187] are related to emotional disorders. ACC, the first-order cortical region that responds to painful stimuli [188], plays an important role in pain information processing [189,190,191], including the processing of pain affection [192,193,194,195]. Abnormal expression of TNF-α, neuronal hyperexcitability and microglial activation in ACC contribute to inflammatory and neuropathic pain and pain aversion [20,196]. Studies have shown that pharmacologically blocking neuroinflammation and activation of glial cells of ACC reduces chronic pain and prevents the occurrence of accompanying emotional disorders or memory deficits caused by complete Freund’s adjuvant (CFA), the chemotherapeutic drug oxaliplatin or peripheral nerve injury [20,197,198].
Earlier studies have confirmed that in patients with severe depression, the loss of glial cells and reduction of neuronal size occur in the deeper cortical layers in ACC and the dorsolateral prefrontal cortex [199,200]. RIPK1, the key protein initiating RIPK3/MLKL-dependent necroptosis [201], promotes ischaemia-induced neuronal and astrocytic cell death [202]. A study reported that depression induced by chronic unpredictable mild stress (CUMS) led to anxiety-like behaviour but did not damage spatial learning and memory, which was accompanied by the expression of RIPK3/MLKL and activation of necroptosis [203]. Pharmacological or genetic regulation of necroptosis alleviates depressive or anxiety-like behaviour and improves hippocampal function and neuroinflammation [204]. Recently, the relationship between oligodendrocytes and emotional disorders has been receiving increasing attention [205,206,207,208,209,210]. In addition to the activation of microglia and impairment of astrocytic function, a reduction in the number or density of oligodendrocytes is one of the most prominent observations in depression [211]. Inflammatory cytokines from oligodendrocytes have been implicated in the pathological process of depression [212,213]. Inhibiting the activity of oligodendrocytes using a chemogenetic approach leads to depression-like behavior and increases TNF-α-induced oligodendrocyte necroptosis through interaction with TNFR1 [214]. Although studies reporting on the role of the TNF-α–necroptosis pathway in pain-associated mood disorders are lacking, research prospects of this pathway in the field of neuroscience can be predicted based on the above mentioned studies.

4.5. TNF-α/Necroptosis in Pain-Associated Memory Deficits

Depression is closely related to a decline in cognitive abilities such as concentration and memory difficulties [215] with a decreased volume of the hippocampal brain region [216]. These cognitive impairments are commonly related to chronic pain [217,218]. Decreased hippocampal volume can be observed in patients with chronic pathological pain such as chronic back pain, complex regional pain syndrome [219] and knee osteoarthritis [220]. Clinical studies have shown that chronic pain accompanied by a reduction in the hippocampal volume can significantly reduce the learning ability of the body [221,222], resulting in short- and long-term memory defects [223]. At present, the widely accepted theory for the mechanism of pain-impaired memory is the alteration of hippocampal synaptic plasticity (long-term potentiation [LTP]), which is considered the molecular mechanism underlying learning and memory [224,225] or that underlying the effects of pain on memory [117,219]. In addition, morphological and biochemical changes in the hippocampal region underlie cognitive impairment in neuropathic pain [226].
Upregulation of TNF-α [117,227,228], a decrease in the expression of brain-derived neurotrophic factor (BDNF) and microglial activation [226,227] in the hippocampus may be the basis of chronic pain and memory defects. Blocking nerve injury-induced hippocampal TNF-α via oral administration of magnesium L-threonine, a new method of preventing neuropathic pain caused by chemotherapy [229] or using nanocurcumin can improve pain and memory impairment [117,230]. At present, whether TNF-α mediates pain-associated cognitive deficits by activating necroptosis remains unclear; however, its role has been reported in other neurodegenerative diseases. For example, necroptosis mediates TNF-α-induced toxicity of hippocampal neurons [231], leading to memory impairment in AD [159,232,233]. Inhibiting necroptosis and abnormally high expression of TNF-α in the hippocampus can reduce cell death and improve cognitive ability [159,234,235,236].

5. Conclusions

The neuroimmune mechanisms underlying neuropathic pain are complex and involve many factors, including inflammatory and anti-inflammatory imbalances that in the most severe form is called cytokine storm. For example, spinal formyl peptide receptor type 2 (FPR2/ALX), a member of the formyl peptide receptors family, plays an analgesic role by reducing cytokines and BDNF [237]. This review focuses on the potential mechanisms of proinflammatory cytokine TNF-α-mediated neuropathic pain and discusses the role of TNF-α-necroptosis pathway in detail. As shown in Figure 2, TNF-α, as a crucial driver, can regulate cation channels to sensitize primary afferents in the peripheral nervous system, affect excitatory and inhibitory synaptic transmissions in CNS and evoke positive feedback between TNF-α and microglial activation to induce neuroinflammation, thus facilitating pain transmission, adverse pain-associated emotional reactions and cognitive deficits. TNF-α-triggered necroptosis, a novel form of programmed cell death, may be one of the key factors for inducing neuroimmune responses in neuropathic pain. It not only contributes to allodynia and hyperalgesia but also mediates aversion, anxiety, depression and learning and memory deficits associated with chronic pain. Therefore, understanding the important role of the TNF-α–necroptosis pathway in neuropathic pain may offer novel strategies for the treatment of neurological diseases.

Author Contributions

Conceptualization, Y.-W.D., S.-X.C. and Y.Z.; methodology, Y.-W.D.; software, Y.-W.D.; validation, Y.-W.D., S.-X.C. and Q.-Y.L.; formal analysis, S.-X.C.; investigation, Y.-W.D. and S.-X.C.; resources, Y.-W.D. and S.-X.C.; data curation, Y.Z.; writing—original draft preparation, Y.-W.D. and S.-X.C.; writing—review and editing, Y.Z.; visualization, Y.-W.D.; supervision, Y.Z.; project administration, Y.Z.; funding acquisition, Y.Z. and S.-X.C. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by the National Natural Science Foundation of China (Grant No. 81870873 and 81801111) and the Natural Science Foundation of Guangdong Province of China (Grant No. 2022A1515012198).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data were retrieved with the theme of “necroptosis” from the Division of Neuroscience in the core database of the Web of Science (WoS).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Gupta, K.K.; Khan, M.A.; Singh, S.K. Constitutive Inflammatory Cytokine Storm: A Major Threat to Human Health. J. Interferon Cytokine Res. 2020, 40, 19–23. [Google Scholar] [CrossRef]
  2. Gilron, I.; Watson, C.P.; Cahill, C.M.; Moulin, D.E. Neuropathic pain: A practical guide for the clinician. Cmaj 2006, 175, 265–275. [Google Scholar] [CrossRef] [Green Version]
  3. Sommer, C. Painful neuropathies. Curr. Opin. Neurol. 2003, 16, 623–628. [Google Scholar] [CrossRef] [Green Version]
  4. Basbaum, A.I. Distinct neurochemical features of acute and persistent pain. Proc. Natl. Acad. Sci. USA 1999, 96, 7739–7743. [Google Scholar] [CrossRef] [Green Version]
  5. Costigan, M.; Scholz, J.; Woolf, C.J. Neuropathic pain: A maladaptive response of the nervous system to damage. Annu. Rev. Neurosci. 2009, 32, 1–32. [Google Scholar] [CrossRef] [Green Version]
  6. Finnerup, N.B.; Attal, N.; Haroutounian, S.; McNicol, E.; Baron, R.; Dworkin, R.H.; Gilron, I.; Haanpaa, M.; Hansson, P.; Jensen, T.S.; et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015, 14, 162–173. [Google Scholar] [CrossRef] [Green Version]
  7. Gilron, I.; Baron, R.; Jensen, T. Neuropathic pain: Principles of diagnosis and treatment. Mayo Clin. Proc. 2015, 90, 532–545. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  8. Kuffler, D.P. Mechanisms for Reducing Neuropathic Pain. Mol. Neurobiol. 2020, 57, 67–87. [Google Scholar] [CrossRef]
  9. Sobeh, M.; Mahmoud, M.F.; Rezq, S.; Alsemeh, A.E.; Sabry, O.M.; Mostafa, I.; Abdelfattah, M.A.O.; El-Allem, K.A.; El-Shazly, A.M.; Yasri, A.; et al. Salix tetrasperma Roxb. Extract Alleviates Neuropathic Pain in Rats via Modulation of the NF-kappaB/TNF-alpha/NOX/iNOS Pathway. Antioxidants 2019, 8, 482. [Google Scholar] [CrossRef] [Green Version]
  10. Woolf, C.J.; Mannion, R.J. Neuropathic pain: Aetiology, symptoms, mechanisms, and management. Lancet 1999, 353, 1959–1964. [Google Scholar] [CrossRef]
  11. Zimmermann, M. Pathobiology of neuropathic pain. Eur. J. Pharmacol. 2001, 429, 23–37. [Google Scholar] [CrossRef]
  12. Baron, R.; Binder, A.; Wasner, G. Neuropathic pain: Diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol. 2010, 9, 807–819. [Google Scholar] [CrossRef]
  13. Colloca, L.; Ludman, T.; Bouhassira, D.; Baron, R.; Dickenson, A.H.; Yarnitsky, D.; Freeman, R.; Truini, A.; Attal, N.; Finnerup, N.B.; et al. Neuropathic pain. Nat. Rev. Dis. Primers 2017, 3, 17002. [Google Scholar] [CrossRef] [Green Version]
  14. Dieleman, J.P.; Kerklaan, J.; Huygen, F.; Bouma, P.A.D.; Sturkenboom, M. Incidence rates and treatment of neuropathic pain conditions in the general population. Pain 2008, 137, 681–688. [Google Scholar] [CrossRef]
  15. Jensen, T.S.; Baron, R.; Haanpaa, M.; Kalso, E.; Loeser, J.D.; Rice, A.S.C.; Treede, R.D. A new definition of neuropathic pain. Pain 2011, 152, 2204–2205. [Google Scholar] [CrossRef]
  16. Blyth, F.M. Global burden of neuropathic pain. Pain 2018, 159, 614–617. [Google Scholar] [CrossRef]
  17. McDermott, A.M.; Toelle, T.R.; Rowbotham, D.J.; Schaefer, C.P.; Dukes, E.M. The burden of neuropathic pain: Results from a cross-sectional survey. Eur. J. Pain 2006, 10, 127–135. [Google Scholar] [CrossRef]
  18. O’Connor, A.B. Neuropathic pain: Quality-of-life impact, costs and cost effectiveness of therapy. Pharmacoeconomics 2009, 27, 95–112. [Google Scholar] [CrossRef]
  19. Rosberg, H.E.; Carlsson, K.S.; Cederlund, R.I.; Ramel, E.; Dahlin, L.B. Costs and outcome for serious hand and arm injuries during the first year after trauma—A prospective study. BMC Public Health 2013, 13, 501. [Google Scholar] [CrossRef] [Green Version]
  20. Yao, P.W.; Wang, S.K.; Chen, S.X.; Xin, W.J.; Liu, X.G.; Zang, Y. Upregulation of tumor necrosis factor-alpha in the anterior cingulate cortex contributes to neuropathic pain and pain-associated aversion. Neurobiol. Dis. 2019, 130, 104456. [Google Scholar] [CrossRef]
  21. Chen, S.X.; Liao, G.J.; Yao, P.W.; Wang, S.K.; Li, Y.Y.; Zeng, W.A.; Liu, X.G.; Zang, Y. Calpain-2 Regulates TNF-alpha Expression Associated with Neuropathic Pain Following Motor Nerve Injury. Neuroscience 2018, 376, 142–151. [Google Scholar] [CrossRef] [PubMed]
  22. Chen, S.X.; Wang, S.K.; Yao, P.W.; Liao, G.J.; Na, X.D.; Li, Y.Y.; Zeng, W.A.; Liu, X.G.; Zang, Y. Early CALP2 expression and microglial activation are potential inducers of spinal IL-6 up-regulation and bilateral pain following motor nerve injury. J. Neurochem. 2018, 145, 154–169. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. He, X.H.; Zang, Y.; Chen, X.; Pang, R.P.; Xu, J.T.; Zhou, X.; Wei, X.H.; Li, Y.Y.; Xin, W.J.; Qin, Z.H.; et al. TNF-alpha contributes to up-regulation of Nav1.3 and Nav1.8 in DRG neurons following motor fiber injury. Pain 2010, 151, 266–279. [Google Scholar] [CrossRef] [PubMed]
  24. Zang, Y.; Chen, S.X.; Liao, G.J.; Zhu, H.Q.; Wei, X.H.; Cui, Y.; Na, X.D.; Pang, R.P.; Xin, W.J.; Zhou, L.J.; et al. Calpain-2 contributes to neuropathic pain following motor nerve injury via up-regulating interleukin-6 in DRG neurons. Brain Behav. Immun. 2015, 44, 37–47. [Google Scholar] [CrossRef]
  25. Zang, Y.; He, X.H.; Xin, W.J.; Pang, R.P.; Wei, X.H.; Zhou, L.J.; Li, Y.Y.; Liu, X.G. Inhibition of NF-kappaB prevents mechanical allodynia induced by spinal ventral root transection and suppresses the re-expression of Nav1.3 in DRG neurons in vivo and in vitro. Brain Res. 2010, 1363, 151–158. [Google Scholar] [CrossRef]
  26. Sweitzer, S.M.; Hickey, W.F.; Rutkowski, M.D.; Pahl, J.L.; DeLeo, J.A. Focal peripheral nerve injury induces leukocyte trafficking into the central nervous system: Potential relationship to neuropathic pain. Pain 2002, 100, 163–170. [Google Scholar] [CrossRef]
  27. Grace, P.M.; Tawfik, V.L.; Svensson, C.I.; Burton, M.D.; Loggia, M.L.; Hutchinson, M.R. The Neuroimmunology of Chronic Pain: From Rodents to Humans. J. Neurosci. 2021, 41, 855–865. [Google Scholar] [CrossRef]
  28. Moalem, G.; Tracey, D.J. Immune and inflammatory mechanisms in neuropathic pain. Brain Res. Rev. 2006, 51, 240–264. [Google Scholar] [CrossRef]
  29. Kuner, R. Central mechanisms of pathological pain. Nat. Med. 2010, 16, 1258–1266. [Google Scholar] [CrossRef]
  30. Li, L.; Xian, C.J.; Zhong, J.H.; Zhou, X.F. Lumbar 5 ventral root transection-induced upregulation of nerve growth factor in sensory neurons and their target tissues: A mechanism in neuropathic pain. Mol. Cell. Neurosci. 2003, 23, 232–250. [Google Scholar] [CrossRef]
  31. Li, L.; Xian, C.J.; Zhong, J.H.; Zhou, X.F. Effect of lumbar 5 ventral root transection on pain behaviors: A novel rat model for neuropathic pain without axotomy of primary sensory neurons. Exp. Neurol. 2002, 175, 23–34. [Google Scholar] [CrossRef] [PubMed]
  32. Obata, K.; Yamanaka, H.; Kobayashi, K.; Dai, Y.; Mizushima, T.; Katsura, H.; Fukuoka, T.; Tokunaga, A.; Noguchi, K. The effect of site and type of nerve injury on the expression of brain-derived neurotrophic factor in the dorsal root ganglion and on neuropathic pain behavior. Neuroscience 2006, 137, 961–970. [Google Scholar] [CrossRef] [PubMed]
  33. Sheth, R.N.; Dorsi, M.J.; Li, Y.; Murinson, B.B.; Belzberg, A.J.; Griffin, J.W.; Meyer, R.A. Mechanical hyperalgesia after an L5 ventral rhizotomy or an L5 ganglionectomy in the rat. Pain 2002, 96, 63–72. [Google Scholar] [CrossRef]
  34. Wu, G.; Ringkamp, M.; Murinson, B.B.; Pogatzki, E.M.; Hartke, T.V.; Weerahandi, H.M.; Campbell, J.N.; Griffin, J.W.; Meyer, R.A. Degeneration of myelinated efferent fibers induces spontaneous activity in uninjured C-fiber afferents. J. Neurosci. 2002, 22, 7746–7753. [Google Scholar] [CrossRef]
  35. Sorkin, L.S.; Doom, C.M. Epineurial application of TNF elicits an acute mechanical hyperalgesia in the awake rat. J. Peripher. Nerv. Syst. 2000, 5, 96–100. [Google Scholar] [CrossRef]
  36. Zelenka, M.; Schafers, M.; Sommer, C. Intraneural injection of interleukin-1beta and tumor necrosis factor-alpha into rat sciatic nerve at physiological doses induces signs of neuropathic pain. Pain 2005, 116, 257–263. [Google Scholar] [CrossRef]
  37. Nimmerjahn, A.; Kirchhoff, F.; Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005, 308, 1314–1318. [Google Scholar] [CrossRef] [Green Version]
  38. Ransohoff, R.M.; Cardona, A.E. The myeloid cells of the central nervous system parenchyma. Nature 2010, 468, 253–262. [Google Scholar] [CrossRef]
  39. Sanchez-Molina, P.; Almolda, B.; Benseny-Cases, N.; Gonzalez, B.; Peralvarez-Marin, A.; Castellano, B. Specific microglial phagocytic phenotype and decrease of lipid oxidation in white matter areas during aging: Implications of different microenvironments. Neurobiol. Aging 2021, 105, 280–295. [Google Scholar] [CrossRef]
  40. Shields, D.C.; Haque, A.; Banik, N.L. Neuroinflammatory responses of microglia in central nervous system trauma. J. Cereb. Blood Flow Metab. 2020, 40, S25–S33. [Google Scholar] [CrossRef]
  41. Veremeyko, T.; Yung, A.W.Y.; Dukhinova, M.; Strekalova, T.; Ponomarev, E.D. The Role of Neuronal Factors in the Epigenetic Reprogramming of Microglia in the Normal and Diseased Central Nervous System. Front. Cell. Neurosci. 2019, 13, 453. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. McCarthy, M.M. Location, Location, Location: Microglia Are Where They Live. Neuron 2017, 95, 233–235. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Lee, S.; Zhao, Y.Q.; Ribeiro-da-Silva, A.; Zhang, J. Distinctive response of CNS glial cells in oro-facial pain associated with injury, infection and inflammation. Mol. Pain 2010, 6, 79. [Google Scholar] [CrossRef] [Green Version]
  44. Mallard, C.; Tremblay, M.E.; Vexler, Z.S. Microglia and Neonatal Brain Injury. Neuroscience 2019, 405, 68–76. [Google Scholar] [CrossRef]
  45. Aldskogius, H.; Kozlova, E.N. Central neuron-glial and glial-glial interactions following axon injury. Prog. Neurobiol. 1998, 55, 1–26. [Google Scholar] [CrossRef]
  46. Lee, J.; Hwang, H.; Lee, S.J. Distinct roles of GT1b and CSF-1 in microglia activation in nerve injury-induced neuropathic pain. Mol. Pain 2021, 17, 17448069211020918. [Google Scholar] [CrossRef]
  47. Aldskogius, H. Mechanisms and consequences of microglial responses to peripheral axotomy. Front. Biosci. 2011, 3, 857–868. [Google Scholar] [CrossRef] [Green Version]
  48. Kuhn, J.A.; Vainchtein, I.D.; Braz, J.; Hamel, K.; Bernstein, M.; Craik, V.; Dahlgren, M.W.; Ortiz-Carpena, J.; Molofsky, A.B.; Molofsky, A.V.; et al. Regulatory T-cells inhibit microglia-induced pain hypersensitivity in female mice. Elife 2021, 10, e69056. [Google Scholar] [CrossRef]
  49. Reischer, G.; Heinke, B.; Sandkuhler, J. Interferon-gamma facilitates the synaptic transmission between primary afferent C-fibres and lamina I neurons in the rat spinal dorsal horn via microglia activation. Mol. Pain 2020, 16, 1744806920917249. [Google Scholar] [CrossRef] [Green Version]
  50. Yamamoto, Y.; Terayama, R.; Kishimoto, N.; Maruhama, K.; Mizutani, M.; Iida, S.; Sugimoto, T. Activated microglia contribute to convergent nociceptive inputs to spinal dorsal horn neurons and the development of neuropathic pain. Neurochem. Res. 2015, 40, 1000–1012. [Google Scholar] [CrossRef]
  51. Clark, A.K.; Yip, P.K.; Grist, J.; Gentry, C.; Staniland, A.A.; Marchand, F.; Dehvari, M.; Wotherspoon, G.; Winter, J.; Ullah, J.; et al. Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc. Natl. Acad. Sci. USA 2007, 104, 10655–10660. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Beggs, S.; Salter, M.W. Stereological and somatotopic analysis of the spinal microglial response to peripheral nerve injury. Brain Behav. Immun. 2007, 21, 624–633. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Lloyd, A.F.; Davies, C.L.; Holloway, R.K.; Labrak, Y.; Ireland, G.; Carradori, D.; Dillenburg, A.; Borger, E.; Soong, D.; Richardson, J.C.; et al. Central nervous system regeneration is driven by microglia necroptosis and repopulation. Nat. Neurosci. 2019, 22, 1046–1052. [Google Scholar] [CrossRef] [PubMed]
  54. Holler, N.; Zaru, R.; Micheau, O.; Thome, M.; Attinger, A.; Valitutti, S.; Bodmer, J.L.; Schneider, P.; Seed, B.; Tschopp, J. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat. Immunol. 2000, 1, 489–495. [Google Scholar] [CrossRef]
  55. Newton, K.; Manning, G. Necroptosis and Inflammation. Annu. Rev. Biochem. 2016, 85, 743–763. [Google Scholar] [CrossRef]
  56. Kalliolias, G.D.; Ivashkiv, L.B. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat. Rev. Rheumatol. 2016, 12, 49–62. [Google Scholar] [CrossRef]
  57. Chen, A.Q.; Fang, Z.; Chen, X.L.; Yang, S.; Zhou, Y.F.; Mao, L.; Xia, Y.P.; Jin, H.J.; Li, Y.N.; You, M.F.; et al. Microglia-derived TNF-alpha mediates endothelial necroptosis aggravating blood brain-barrier disruption after ischemic stroke. Cell Death Dis. 2019, 10, 487. [Google Scholar] [CrossRef]
  58. Cai, Z.Y.; Jitkaew, S.; Zhao, J.; Chiang, H.C.; Choksi, S.; Liu, J.; Ward, Y.; Wu, L.G.; Liu, Z.G. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat. Cell Biol. 2014, 16, 55–65. [Google Scholar] [CrossRef]
  59. Feoktistova, M.; Makarov, R.; Yazdi, A.S.; Panayotova-Dimitrova, D. RIPK1 and TRADD Regulate TNF-Induced Signaling and Ripoptosome Formation. Int. J. Mol. Sci. 2021, 22, 12459. [Google Scholar] [CrossRef]
  60. Galluzzi, L.; Kepp, O.; Chan, F.K.; Kroemer, G. Necroptosis: Mechanisms and Relevance to Disease. Annu. Rev. Pathol. 2017, 12, 103–130. [Google Scholar] [CrossRef]
  61. Pasparakis, M.; Vandenabeele, P. Necroptosis and its role in inflammation. Nature 2015, 517, 311–320. [Google Scholar] [CrossRef] [PubMed]
  62. Chen, J.; Kos, R.; Garssen, J.; Redegeld, F. Molecular Insights into the Mechanism of Necroptosis: The Necrosome As a Potential Therapeutic Target. Cells 2019, 8, 1486. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Tummers, B.; Green, D.R. Caspase-8: Regulating life and death. Immunol. Rev. 2017, 277, 76–89. [Google Scholar] [CrossRef] [Green Version]
  64. Micheau, O.; Tschopp, J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 2003, 114, 181–190. [Google Scholar] [CrossRef] [Green Version]
  65. Degterev, A.; Huang, Z.; Boyce, M.; Li, Y.; Jagtap, P.; Mizushima, N.; Cuny, G.D.; Mitchison, T.J.; Moskowitz, M.A.; Yuan, J. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat. Chem. Biol. 2005, 1, 112–119. [Google Scholar] [CrossRef] [PubMed]
  66. Oberst, A.; Dillon, C.P.; Weinlich, R.; McCormick, L.L.; Fitzgerald, P.; Pop, C.; Hakem, R.; Salvesen, G.S.; Green, D.R. Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis. Nature 2011, 471, 363–367. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Wang, H.; Sun, L.; Su, L.; Rizo, J.; Liu, L.; Wang, L.F.; Wang, F.S.; Wang, X. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol. Cell 2014, 54, 133–146. [Google Scholar] [CrossRef] [Green Version]
  68. Shamash, S.; Reichert, F.; Rotshenker, S. The cytokine network of Wallerian degeneration: Tumor necrosis factor-alpha, interleukin-1alpha, and interleukin-1beta. J. Neurosci. 2002, 22, 3052–3060. [Google Scholar] [CrossRef] [Green Version]
  69. Sacerdote, P.; Franchi, S.; Trovato, A.E.; Valsecchi, A.E.; Panerai, A.E.; Colleoni, M. Transient early expression of TNF-alpha in sciatic nerve and dorsal root ganglia in a mouse model of painful peripheral neuropathy. Neurosci. Lett. 2008, 436, 210–213. [Google Scholar] [CrossRef]
  70. Schafers, M.; Sorkin, L.S.; Geis, C.; Shubayev, V.I. Spinal nerve ligation induces transient upregulation of tumor necrosis factor receptors 1 and 2 in injured and adjacent uninjured dorsal root ganglia in the rat. Neurosci. Lett. 2003, 347, 179–182. [Google Scholar] [CrossRef]
  71. Wei, X.H.; Zang, Y.; Wu, C.Y.; Xu, J.T.; Xin, W.J.; Liu, X.G. Peri-sciatic administration of recombinant rat TNF-alpha induces mechanical allodynia via upregulation of TNF-alpha in dorsal root ganglia and in spinal dorsal horn: The role of NF-kappa B pathway. Exp. Neurol. 2007, 205, 471–484. [Google Scholar] [CrossRef] [PubMed]
  72. Covey, W.C.; Ignatowski, T.A.; Renauld, A.E.; Knight, P.R.; Nader, N.D.; Spengler, R.N. Expression of neuron-associated tumor necrosis factor alpha in the brain is increased during persistent pain. Reg. Anesth. Pain Med. 2002, 27, 357–366. [Google Scholar] [PubMed]
  73. Ignatowski, T.A.; Covey, W.C.; Knight, P.R.; Severin, C.M.; Nickola, T.J.; Spengler, R.N. Brain-derived TNFalpha mediates neuropathic pain. Brain Res. 1999, 841, 70–77. [Google Scholar] [CrossRef]
  74. Covey, W.C.; Ignatowski, T.A.; Knight, P.R.; Spengler, R.N. Brain-derived TNFalpha: Involvement in neuroplastic changes implicated in the conscious perception of persistent pain. Brain Res. 2000, 859, 113–122. [Google Scholar] [CrossRef]
  75. Zhao, Y.F.; Yang, H.W.; Yang, T.S.; Xie, W.X.; Hu, Z.H. TNF-alpha-mediated peripheral and central inflammation are associated with increased incidence of PND in acute postoperative pain. Bmc Anesthesiol. 2021, 21, 79. [Google Scholar] [CrossRef]
  76. Clark, I.A. How TNF was recognized as a key mechanism of disease. Cytokine Growth Factor Rev. 2007, 18, 335–343. [Google Scholar] [CrossRef]
  77. Leung, L.; Cahill, C.M. TNF-alpha and neuropathic pain—A review. J. Neuroinflamm. 2010, 7, 27. [Google Scholar] [CrossRef] [Green Version]
  78. Zhang, H.; Nei, H.; Dougherty, P.M. A p38 mitogen-activated protein kinase-dependent mechanism of disinhibition in spinal synaptic transmission induced by tumor necrosis factor-alpha. J. Neurosci. 2010, 30, 12844–12855. [Google Scholar] [CrossRef]
  79. Opree, A.; Kress, M. Involvement of the proinflammatory cytokines tumor necrosis factor-alpha, IL-1 beta, and IL-6 but not IL-8 in the development of heat hyperalgesia: Effects on heat-evoked calcitonin gene-related peptide release from rat skin. J. Neurosci. 2000, 20, 6289–6293. [Google Scholar] [CrossRef]
  80. Junger, H.; Sorkin, L.S. Nociceptive and inflammatory effects of subcutaneous TNFalpha. Pain 2000, 85, 145–151. [Google Scholar] [CrossRef]
  81. Liu, B.; Li, H.; Brull, S.J.; Zhang, J.M. Increased sensitivity of sensory neurons to tumor necrosis factor alpha in rats with chronic compression of the lumbar ganglia. J. Neurophysiol. 2002, 88, 1393–1399. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Schafers, M.; Lee, D.H.; Brors, D.; Yaksh, T.L.; Sorkin, L.S. Increased sensitivity of injured and adjacent uninjured rat primary sensory neurons to exogenous tumor necrosis factor-alpha after spinal nerve ligation. J. Neurosci. 2003, 23, 3028–3038. [Google Scholar] [CrossRef] [PubMed]
  83. Zhang, J.M.; Li, H.; Liu, B.; Brull, S.J. Acute topical application of tumor necrosis factor alpha evokes protein kinase A-dependent responses in rat sensory neurons. J. Neurophysiol. 2002, 88, 1387–1392. [Google Scholar] [CrossRef] [PubMed]
  84. Zhang, X.L.; Ding, H.H.; Xu, T.; Liu, M.; Ma, C.; Wu, S.L.; Wei, J.Y.; Liu, C.C.; Zhang, S.B.; Xin, W.J. Palmitoylation of delta-catenin promotes kinesin-mediated membrane trafficking of Nav1.6 in sensory neurons to promote neuropathic pain. Sci. Signal. 2018, 11, eaar4394. [Google Scholar] [CrossRef] [Green Version]
  85. Leo, M.; Argalski, S.; Schafers, M.; Hagenacker, T. Modulation of Voltage-Gated Sodium Channels by Activation of Tumor Necrosis Factor Receptor-1 and Receptor-2 in Small DRG Neurons of Rats. Mediat. Inflamm. 2015, 2015, 124942. [Google Scholar] [CrossRef] [Green Version]
  86. Wu, Z.; Wang, S.; Gruber, S.; Mata, M.; Fink, D.J. Full-length membrane-bound tumor necrosis factor-alpha acts through tumor necrosis factor receptor 2 to modify phenotype of sensory neurons. Pain 2013, 154, 1778–1782. [Google Scholar] [CrossRef] [Green Version]
  87. Jin, X.; Gereau, R.W.t. Acute p38-mediated modulation of tetrodotoxin-resistant sodium channels in mouse sensory neurons by tumor necrosis factor-alpha. J. Neurosci. 2006, 26, 246–255. [Google Scholar] [CrossRef]
  88. Sole, L.; Wagnon, J.L.; Akin, E.J.; Meisler, M.H.; Tamkun, M.M. The MAP1B Binding Domain of Nav1.6 Is Required for Stable Expression at the Axon Initial Segment. J. Neurosci. 2019, 39, 4238–4251. [Google Scholar] [CrossRef] [Green Version]
  89. Sittl, R.; Lampert, A.; Huth, T.; Schuy, E.T.; Link, A.S.; Fleckenstein, J.; Alzheimer, C.; Grafe, P.; Carr, R.W. Anticancer drug oxaliplatin induces acute cooling-aggravated neuropathy via sodium channel subtype Na(V)1.6-resurgent and persistent current. Proc. Natl. Acad. Sci. USA 2012, 109, 6704–6709. [Google Scholar] [CrossRef] [Green Version]
  90. Xie, W.; Zhang, J.; Strong, J.A.; Zhang, J.M. Role of NaV1.6 and NaVbeta4 Sodium Channel Subunits in a Rat Model of Low Back Pain Induced by Compression of the Dorsal Root Ganglia. Neuroscience 2019, 402, 51–65. [Google Scholar] [CrossRef]
  91. Chen, L.; Huang, J.; Benson, C.; Lankford, K.L.; Zhao, P.; Carrara, J.; Tan, A.M.; Kocsis, J.D.; Waxman, S.G.; Dib-Hajj, S.D. Sodium channel Nav1.6 in sensory neurons contributes to vincristine-induced allodynia. Brain 2020, 143, 2421–2436. [Google Scholar] [CrossRef] [PubMed]
  92. Xie, W.; Strong, J.A.; Ye, L.; Mao, J.X.; Zhang, J.M. Knockdown of sodium channel NaV1.6 blocks mechanical pain and abnormal bursting activity of afferent neurons in inflamed sensory ganglia. Pain 2013, 154, 1170–1180. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Chen, L.; Huang, J.; Zhao, P.; Persson, A.K.; Dib-Hajj, F.B.; Cheng, X.; Tan, A.; Waxman, S.G.; Dib-Hajj, S.D. Conditional knockout of NaV1.6 in adult mice ameliorates neuropathic pain. Sci Rep 2018, 8, 3845. [Google Scholar] [CrossRef] [PubMed]
  94. Ding, H.H.; Zhang, S.B.; Lv, Y.Y.; Ma, C.; Liu, M.; Zhang, K.B.; Ruan, X.C.; Wei, J.Y.; Xin, W.J.; Wu, S.L. TNF-alpha/STAT3 pathway epigenetically upregulates Nav1.6 expression in DRG and contributes to neuropathic pain induced by L5-VRT. J. Neuroinflamm. 2019, 16, 29. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Cox, J.J.; Reimann, F.; Nicholas, A.K.; Thornton, G.; Roberts, E.; Springell, K.; Karbani, G.; Jafri, H.; Mannan, J.; Raashid, Y.; et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature 2006, 444, 894–898. [Google Scholar] [CrossRef]
  96. Dib-Hajj, S.D.; Cummins, T.R.; Black, J.A.; Waxman, S.G. Sodium channels in normal and pathological pain. Annu. Rev. Neurosci. 2010, 33, 325–347. [Google Scholar] [CrossRef] [Green Version]
  97. McDermott, L.A.; Weir, G.A.; Themistocleous, A.C.; Segerdahl, A.R.; Blesneac, I.; Baskozos, G.; Clark, A.J.; Millar, V.; Peck, L.J.; Ebner, D.; et al. Defining the Functional Role of NaV1.7 in Human Nociception. Neuron 2019, 101, 905–919.e908. [Google Scholar] [CrossRef] [Green Version]
  98. Fertleman, C.R.; Baker, M.D.; Parker, K.A.; Moffatt, S.; Elmslie, F.V.; Abrahamsen, B.; Ostman, J.; Klugbauer, N.; Wood, J.N.; Gardiner, R.M.; et al. SCN9A mutations in paroxysmal extreme pain disorder: Allelic variants underlie distinct channel defects and phenotypes. Neuron 2006, 52, 767–774. [Google Scholar] [CrossRef] [Green Version]
  99. Minett, M.S.; Nassar, M.A.; Clark, A.K.; Passmore, G.; Dickenson, A.H.; Wang, F.; Malcangio, M.; Wood, J.N. Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons. Nat. Commun. 2012, 3, 791. [Google Scholar] [CrossRef] [Green Version]
  100. Nassar, M.A.; Stirling, L.C.; Forlani, G.; Baker, M.D.; Matthews, E.A.; Dickenson, A.H.; Wood, J.N. Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain. Proc. Natl. Acad. Sci. USA 2004, 101, 12706–12711. [Google Scholar] [CrossRef] [Green Version]
  101. Shields, S.D.; Cheng, X.; Uceyler, N.; Sommer, C.; Dib-Hajj, S.D.; Waxman, S.G. Sodium channel Na(v)1.7 is essential for lowering heat pain threshold after burn injury. J. Neurosci. 2012, 32, 10819–10832. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Li, Y.; North, R.Y.; Rhines, L.D.; Tatsui, C.E.; Rao, G.; Edwards, D.D.; Cassidy, R.M.; Harrison, D.S.; Johansson, C.A.; Zhang, H.; et al. DRG Voltage-Gated Sodium Channel 1.7 Is Upregulated in Paclitaxel-Induced Neuropathy in Rats and in Humans with Neuropathic Pain. J. Neurosci. 2018, 38, 1124–1136. [Google Scholar] [CrossRef] [PubMed]
  103. Minett, M.S.; Falk, S.; Santana-Varela, S.; Bogdanov, Y.D.; Nassar, M.A.; Heegaard, A.M.; Wood, J.N. Pain without nociceptors? Nav1.7-independent pain mechanisms. Cell Rep. 2014, 6, 301–312. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Tamura, R.; Nemoto, T.; Maruta, T.; Onizuka, S.; Yanagita, T.; Wada, A.; Murakami, M.; Tsuneyoshi, I. Up-regulation of NaV1.7 sodium channels expression by tumor necrosis factor-alpha in cultured bovine adrenal chromaffin cells and rat dorsal root ganglion neurons. Anesth. Analg. 2014, 118, 318–324. [Google Scholar] [CrossRef] [PubMed]
  105. Xie, M.X.; Zhang, X.L.; Xu, J.; Zeng, W.A.; Li, D.; Xu, T.; Pang, R.P.; Ma, K.; Liu, X.G. Nuclear Factor-kappaB Gates Nav1.7 Channels in DRG Neurons via Protein-Protein Interaction. iScience 2019, 19, 623–633. [Google Scholar] [CrossRef] [Green Version]
  106. Li, C.; Deng, T.; Shang, Z.; Wang, D.; Xiao, Y. Blocking TRPA1 and TNF-alpha Signal Improves Bortezomib-Induced Neuropathic Pain. Cell. Physiol. Biochem. 2018, 51, 2098–2110. [Google Scholar] [CrossRef]
  107. Constantin, C.E.; Mair, N.; Sailer, C.A.; Andratsch, M.; Xu, Z.Z.; Blumer, M.J.; Scherbakov, N.; Davis, J.B.; Bluethmann, H.; Ji, R.R.; et al. Endogenous tumor necrosis factor alpha (TNFalpha) requires TNF receptor type 2 to generate heat hyperalgesia in a mouse cancer model. J. Neurosci. 2008, 28, 5072–5081. [Google Scholar] [CrossRef] [Green Version]
  108. Wang, Y.; Feng, C.; He, H.; He, J.; Wang, J.; Li, X.; Wang, S.; Li, W.; Hou, J.; Liu, T.; et al. Sensitization of TRPV1 receptors by TNF-alpha orchestrates the development of vincristine-induced pain. Oncol. Lett. 2018, 15, 5013–5019. [Google Scholar]
  109. Czeschik, J.C.; Hagenacker, T.; Schafers, M.; Busselberg, D. TNF-alpha differentially modulates ion channels of nociceptive neurons. Neurosci. Lett. 2008, 434, 293–298. [Google Scholar] [CrossRef]
  110. Kawasaki, Y.; Zhang, L.; Cheng, J.K.; Ji, R.R. Cytokine mechanisms of central sensitization: Distinct and overlapping role of interleukin-1 beta, interleukin-6, and tumor necrosis factor-beta in regulating synaptic and neuronal activity in the superficial spinal cord. J. Neurosci. 2008, 28, 5189–5194. [Google Scholar] [CrossRef] [Green Version]
  111. Liu, Y.L.; Zhou, L.J.; Hu, N.W.; Xu, J.T.; Wu, C.Y.; Zhang, T.; Li, Y.Y.; Liu, X.G. Tumor necrosis factor-alpha induces long-term potentiation of C-fiber evoked field potentials in spinal dorsal horn in rats with nerve injury: The role of NF-kappa B, JNK and p38 MAPK. Neuropharmacology 2007, 52, 708–715. [Google Scholar] [CrossRef] [PubMed]
  112. Gruber-Schoffnegger, D.; Drdla-Schutting, R.; Honigsperger, C.; Wunderbaldinger, G.; Gassner, M.; Sandkuhler, J. Induction of thermal hyperalgesia and synaptic long-term potentiation in the spinal cord lamina I by TNF-alpha and IL-1beta is mediated by glial cells. J. Neurosci. 2013, 33, 6540–6551. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Garraway, S.M.; Woller, S.A.; Huie, J.R.; Hartman, J.J.; Hook, M.A.; Miranda, R.C.; Huang, Y.J.; Ferguson, A.R.; Grau, J.W. Peripheral noxious stimulation reduces withdrawal threshold to mechanical stimuli after spinal cord injury: Role of tumor necrosis factor alpha and apoptosis. Pain 2014, 155, 2344–2359. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Kanda, H.; Kobayashi, K.; Yamanaka, H.; Okubo, M.; Noguchi, K. Microglial TNFalpha Induces COX2 and PGI2 Synthase Expression in Spinal Endothelial Cells during Neuropathic Pain. eNeuro 2017, 4, ENEURO.0064-17.2017. [Google Scholar] [CrossRef]
  115. Kroenke, K.; Bair, M.J.; Damush, T.M.; Wu, J.; Hoke, S.; Sutherland, J.; Tu, W. Optimized antidepressant therapy and pain self-management in primary care patients with depression and musculoskeletal pain: A randomized controlled trial. JAMA 2009, 301, 2099–2110. [Google Scholar] [CrossRef] [Green Version]
  116. Page, G.G.; Opp, M.R.; Kozachik, S.L. Reduced sleep, stress responsivity, and female sex contribute to persistent inflammation-induced mechanical hypersensitivity in rats. Brain Behav. Immun. 2014, 40, 244–251. [Google Scholar] [CrossRef]
  117. Wang, J.; Liu, Y.; Zhou, L.J.; Wu, Y.; Li, F.; Shen, K.F.; Pang, R.P.; Wei, X.H.; Li, Y.Y.; Liu, X.G. Magnesium L-threonate Prevents and Restores Memory Deficits Associated with Neuropathic Pain by Inhibition of TNF-alpha. Pain Physician 2013, 16, E563–E575. [Google Scholar]
  118. Berryman, C.; Stanton, T.R.; Jane Bowering, K.; Tabor, A.; McFarlane, A.; Lorimer Moseley, G. Evidence for working memory deficits in chronic pain: A systematic review and meta-analysis. Pain 2013, 154, 1181–1196. [Google Scholar] [CrossRef]
  119. Oka, T.; Wakugawa, Y.; Hosoi, M.; Oka, K.; Hori, T. Intracerebroventricular injection of tumor necrosis factor-alpha induces thermal hyperalgesia in rats. Neuroimmunomodulation 1996, 3, 135–140. [Google Scholar] [CrossRef]
  120. Coelho, A.; Fioramonti, J.; Bueno, L. Brain interleukin-1beta and tumor necrosis factor-alpha are involved in lipopolysaccharide-induced delayed rectal allodynia in awake rats. Brain Res. Bull. 2000, 52, 223–228. [Google Scholar] [CrossRef]
  121. Wei, F.; Guo, W.; Zou, S.; Ren, K.; Dubner, R. Supraspinal glial-neuronal interactions contribute to descending pain facilitation. J. Neurosci. 2008, 28, 10482–10495. [Google Scholar] [CrossRef] [PubMed]
  122. Miller, A.H.; Maletic, V.; Raison, C.L. Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression. Biol. Psychiatry 2009, 65, 732–741. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Taylor, A.M.; Mehrabani, S.; Liu, S.; Taylor, A.J.; Cahill, C.M. Topography of microglial activation in sensory- and affect-related brain regions in chronic pain. J. Neurosci. Res 2017, 95, 1330–1335. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  124. da Silva, M.D.; Guginski, G.; Sato, K.L.; Sanada, L.S.; Sluka, K.A.; Santos, A.R.S. Persistent pain induces mood problems and memory loss by the involvement of cytokines, growth factors, and supraspinal glial cells. Brain Behav. Immun. Health 2020, 7, 100118. [Google Scholar] [CrossRef]
  125. Barcelon, E.E.; Cho, W.H.; Jun, S.B.; Lee, S.J. Brain Microglial Activation in Chronic Pain-Associated Affective Disorder. Front. Neurosci. 2019, 13, 213. [Google Scholar] [CrossRef] [Green Version]
  126. Ren, K.; Dubner, R. Neuron-glia crosstalk gets serious: Role in pain hypersensitivity. Curr. Opin. Anesthesiol. 2008, 21, 570–579. [Google Scholar] [CrossRef] [Green Version]
  127. Stellwagen, D.; Beattie, E.C.; Seo, J.Y.; Malenka, R.C. Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J. Neurosci. 2005, 25, 3219–3228. [Google Scholar] [CrossRef] [Green Version]
  128. Xu, D.; Zhao, H.; Gao, H.; Liu, D.; Li, J. Participation of pro-inflammatory cytokines in neuropathic pain evoked by chemotherapeutic oxaliplatin via central GABAergic pathway. Mol. Pain 2018, 14, 1744806918783535. [Google Scholar] [CrossRef] [Green Version]
  129. Zhang, Q.; Yu, J.; Wang, J.; Ding, C.P.; Han, S.P.; Zeng, X.Y.; Wang, J.Y. The Red Nucleus TNF-alpha Participates in the Initiation and Maintenance of Neuropathic Pain Through Different Signaling Pathways. Neurochem. Res. 2015, 40, 1360–1371. [Google Scholar] [CrossRef]
  130. Butler, M.P.; O’Connor, J.J.; Moynagh, P.N. Dissection of tumor-necrosis factor-alpha inhibition of long-term potentiation (LTP) reveals a p38 mitogen-activated protein kinase-dependent mechanism which maps to early-but not late-phase LTP. Neuroscience 2004, 124, 319–326. [Google Scholar] [CrossRef]
  131. Cunningham, A.J.; Murray, C.A.; O’Neill, L.A.; Lynch, M.A.; O’Connor, J.J. Interleukin-1 beta (IL-1 beta) and tumour necrosis factor (TNF) inhibit long-term potentiation in the rat dentate gyrus in vitro. Neurosci. Lett. 1996, 203, 17–20. [Google Scholar] [CrossRef]
  132. Griffin, R.; Nally, R.; Nolan, Y.; McCartney, Y.; Linden, J.; Lynch, M.A. The age-related attenuation in long-term potentiation is associated with microglial activation. J. Neurochem. 2006, 99, 1263–1272. [Google Scholar] [CrossRef] [PubMed]
  133. Pickering, M.; Cumiskey, D.; O’Connor, J.J. Actions of TNF-alpha on glutamatergic synaptic transmission in the central nervous system. Exp. Physiol. 2005, 90, 663–670. [Google Scholar] [CrossRef] [Green Version]
  134. Pickering, M.; O’Connor, J.J. Pro-inflammatory cytokines and their effects in the dentate gyrus. Prog. Brain Res. 2007, 163, 339–354. [Google Scholar] [PubMed]
  135. Tancredi, V.; D’Arcangelo, G.; Grassi, F.; Tarroni, P.; Palmieri, G.; Santoni, A.; Eusebi, F. Tumor necrosis factor alters synaptic transmission in rat hippocampal slices. Neurosci. Lett. 1992, 146, 176–178. [Google Scholar] [CrossRef]
  136. Thorburn, A. Death receptor-induced cell killing. Cell. Signal. 2004, 16, 139–144. [Google Scholar] [CrossRef] [PubMed]
  137. Fontaine, V.; Mohand-Said, S.; Hanoteau, N.; Fuchs, C.; Pfizenmaier, K.; Eisel, U. Neurodegenerative and neuroprotective effects of tumor Necrosis factor (TNF) in retinal ischemia: Opposite roles of TNF receptor 1 and TNF receptor 2. J. Neurosci. 2002, 22, RC216. [Google Scholar] [CrossRef]
  138. Robertson, J.; Beaulieu, J.M.; Doroudchi, M.M.; Durham, H.D.; Julien, J.P.; Mushynski, W.E. Apoptotic death of neurons exhibiting peripherin aggregates is mediated by the proinflammatory cytokine tumor necrosis factor-alpha. J. Cell Biol. 2001, 155, 217–226. [Google Scholar] [CrossRef]
  139. Sekiguchi, M.; Sekiguchi, Y.; Konno, S.; Kobayashi, H.; Homma, Y.; Kikuchi, S. Comparison of neuropathic pain and neuronal apoptosis following nerve root or spinal nerve compression. Eur. Spine J. 2009, 18, 1978–1985. [Google Scholar] [CrossRef] [Green Version]
  140. Liao, M.F.; Yeh, S.R.; Lu, K.T.; Hsu, J.L.; Chao, P.K.; Hsu, H.C.; Peng, C.H.; Lee, Y.L.; Hung, Y.H.; Ro, L.S. Interactions between Autophagy, Proinflammatory Cytokines, and Apoptosis in Neuropathic Pain: Granulocyte Colony Stimulating Factor as a Multipotent Therapy in Rats with Chronic Constriction Injury. Biomedicines 2021, 9, 542. [Google Scholar] [CrossRef]
  141. Laster, S.M.; Wood, J.G.; Gooding, L.R. Tumor necrosis factor can induce both apoptic and necrotic forms of cell lysis. J. Immunol. 1988, 141, 2629–2634. [Google Scholar] [PubMed]
  142. Kawahara, A.; Ohsawa, Y.; Matsumura, H.; Uchiyama, Y.; Nagata, S. Caspase-independent cell killing by Fas-associated protein with death domain. J. Cell Biol. 1998, 143, 1353–1360. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  143. Chan, F.K.; Shisler, J.; Bixby, J.G.; Felices, M.; Zheng, L.; Appel, M.; Orenstein, J.; Moss, B.; Lenardo, M.J. A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses. J. Biol. Chem. 2003, 278, 51613–51621. [Google Scholar] [CrossRef] [Green Version]
  144. Degterev, A.; Hitomi, J.; Germscheid, M.; Ch’en, I.L.; Korkina, O.; Teng, X.; Abbott, D.; Cuny, G.D.; Yuan, C.; Wagner, G.; et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat. Chem. Biol. 2008, 4, 313–321. [Google Scholar] [CrossRef] [Green Version]
  145. Galluzzi, L.; Vitale, I.; Aaronson, S.A.; Abrams, J.M.; Adam, D.; Agostinis, P.; Alnemri, E.S.; Altucci, L.; Amelio, I.; Andrews, D.W.; et al. Molecular mechanisms of cell death: Recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018, 25, 486–541. [Google Scholar] [PubMed]
  146. D’Arcy, M.S. Cell death: A review of the major forms of apoptosis, necrosis and autophagy. Cell Biol. Int. 2019, 43, 582–592. [Google Scholar] [CrossRef]
  147. Dhuriya, Y.K.; Sharma, D. Necroptosis: A regulated inflammatory mode of cell death. J. Neuroinflamm. 2018, 15, 199. [Google Scholar] [CrossRef] [Green Version]
  148. Li, J.; McQuade, T.; Siemer, A.B.; Napetschnig, J.; Moriwaki, K.; Hsiao, Y.S.; Damko, E.; Moquin, D.; Walz, T.; McDermott, A.; et al. The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell 2012, 150, 339–350. [Google Scholar] [CrossRef] [Green Version]
  149. Aria, M.; Cuccurullo, C. bibliometrix: An R-tool for comprehensive science mapping analysis. J. Informetr. 2017, 11, 959–975. [Google Scholar] [CrossRef]
  150. Waltman, L. Software survey: VOSviewer, a computer program for bibliometric mapping. Scientometrics 2010, 84, 523–538. [Google Scholar]
  151. Vandenabeele, P.; Galluzzi, L.; Vanden Berghe, T.; Kroemer, G. Molecular mechanisms of necroptosis: An ordered cellular explosion. Nat. Rev. Mol. Cell Biol. 2010, 11, 700–714. [Google Scholar] [CrossRef] [PubMed]
  152. Sun, L.; Wang, H.; Wang, Z.; He, S.; Chen, S.; Liao, D.; Wang, L.; Yan, J.; Liu, W.; Lei, X.; et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 2012, 148, 213–227. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  153. Cho, Y.S.; Challa, S.; Moquin, D.; Genga, R.; Ray, T.D.; Guildford, M.; Chan, F.K. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 2009, 137, 1112–1123. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Zhang, D.W.; Shao, J.; Lin, J.; Zhang, N.; Lu, B.J.; Lin, S.C.; Dong, M.Q.; Han, J.H. RIP3, an Energy Metabolism Regulator That Switches TNF-Induced Cell Death from Apoptosis to Necrosis. Science 2009, 325, 332–336. [Google Scholar] [CrossRef] [PubMed]
  155. He, S.; Wang, L.; Miao, L.; Wang, T.; Du, F.; Zhao, L.; Wang, X. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 2009, 137, 1100–1111. [Google Scholar] [CrossRef] [Green Version]
  156. Ofengeim, D.; Ito, Y.; Najafov, A.; Zhang, Y.; Shan, B.; DeWitt, J.P.; Ye, J.; Zhang, X.; Chang, A.; Vakifahmetoglu-Norberg, H.; et al. Activation of necroptosis in multiple sclerosis. Cell Rep. 2015, 10, 1836–1849. [Google Scholar] [CrossRef] [Green Version]
  157. Re, D.B.; Le Verche, V.; Yu, C.H.; Amoroso, M.W.; Politi, K.A.; Phani, S.; Ikiz, B.; Hoffmann, L.; Koolen, M.; Nagata, T.; et al. Necroptosis Drives Motor Neuron Death in Models of Both Sporadic and Familial ALS. Neuron 2014, 81, 1001–1008. [Google Scholar] [CrossRef] [Green Version]
  158. Yuan, J.; Amin, P.; Ofengeim, D. Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat. Rev. Neurosci. 2019, 20, 19–33. [Google Scholar] [CrossRef]
  159. Caccamo, A.; Branca, C.; Piras, I.S.; Ferreira, E.; Huentelman, M.J.; Liang, W.S.; Readhead, B.; Dudley, J.T.; Spangenberg, E.E.; Green, K.N.; et al. Necroptosis activation in Alzheimer’s disease. Nat. Neurosci. 2017, 20, 1236–1246. [Google Scholar] [CrossRef]
  160. Wang, P.; Shao, B.Z.; Deng, Z.; Chen, S.; Yue, Z.; Miao, C.Y. Autophagy in ischemic stroke. Prog. Neurobiol. 2018, 163-164, 98–117. [Google Scholar] [CrossRef]
  161. Zhou, H.; Li, D.D.; Zhu, P.J.; Ma, Q.; Toan, S.; Wang, J.; Hu, S.Y.; Chen, Y.D.; Zhang, Y.M. Inhibitory effect of melatonin on necroptosis via repressing the Ripk3-PGAM5-CypD-mPTP pathway attenuates cardiac microvascular ischemia-reperfusion injury. J. Pineal Res. 2018, 65, e12503. [Google Scholar] [CrossRef] [PubMed]
  162. Abdalkader, M.; Lampinen, R.; Kanninen, K.M.; Malm, T.M.; Liddell, J.R. Targeting Nrf2 to Suppress Ferroptosis and Mitochondrial Dysfunction in Neurodegeneration. Front. Neurosci. 2018, 12, 466. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  163. Dingledine, R.; Varvel, N.H.; Dudek, F.E. When and how do seizures kill neurons, and is cell death relevant to epileptogenesis? Adv. Exp. Med. Biol. 2014, 813, 109–122. [Google Scholar] [PubMed] [Green Version]
  164. Summers, D.W.; DiAntonio, A.; Milbrandt, J. Mitochondrial Dysfunction Induces Sarm1-Dependent Cell Death in Sensory Neurons. J. Neurosci. 2014, 34, 9338–9350. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  165. Cai, Z.; Liu, Z.G. Execution of RIPK3-regulated necrosis. Mol. Cell Oncol 2014, 1, e960759. [Google Scholar] [CrossRef] [Green Version]
  166. Newton, K. RIPK1 and RIPK3: Critical regulators of inflammation and cell death. Trends in Cell Biology 2015, 25, 347–353. [Google Scholar] [CrossRef]
  167. Picon, C.; Jayaraman, A.; James, R.; Beck, C.; Gallego, P.; Witte, M.E.; van Horssen, J.; Mazarakis, N.D.; Reynolds, R. Neuron-specific activation of necroptosis signaling in multiple sclerosis cortical grey matter. Acta Neuropathol. 2021, 141, 585–604. [Google Scholar] [CrossRef]
  168. Xu, C.; Wu, J.; Wu, Y.; Ren, Z.; Yao, Y.; Chen, G.; Fang, E.F.; Noh, J.H.; Liu, Y.U.; Wei, L.; et al. TNF-alpha-dependent neuronal necroptosis regulated in Alzheimer’s disease by coordination of RIPK1-p62 complex with autophagic UVRAG. Theranostics 2021, 11, 9452–9469. [Google Scholar] [CrossRef]
  169. Dionisio, P.A.; Amaral, J.D.; Rodrigues, C.M.P. Molecular mechanisms of necroptosis and relevance for neurodegenerative diseases. Cell Death Regul. Health Dis.—Pt C 2020, 353, 31–82. [Google Scholar]
  170. Jayaraman, A.; Htike, T.T.; James, R.; Picon, C.; Reynolds, R. TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer’s disease hippocampus. Acta Neuropathol. Commun. 2021, 9, 159. [Google Scholar] [CrossRef]
  171. Yang, Z.; Li, C.; Wang, Y.S.; Yang, J.R.; Yin, Y.; Liu, M.L.; Shi, Z.L.; Mu, N.; Yu, L.; Ma, H. Melatonin attenuates chronic pain related myocardial ischemic susceptibility through inhibiting RIP3-MLKL/CaMKII dependent necroptosis. J. Mol. Cell. Cardiol. 2018, 125, 185–194. [Google Scholar] [CrossRef] [PubMed]
  172. Yabal, M.; Muller, N.; Adler, H.; Knies, N.; Gross, C.J.; Damgaard, R.B.; Kanegane, H.; Ringelhan, M.; Kaufmann, T.; Heikenwalder, M.; et al. XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation. Cell Rep. 2014, 7, 1796–1808. [Google Scholar] [CrossRef] [Green Version]
  173. Wallach, D.; Kang, T.B.; Dillon, C.P.; Green, D.R. Programmed necrosis in inflammation: Toward identification of the effector molecules. Science 2016, 352, aaf2154. [Google Scholar] [CrossRef]
  174. Koehler, H.; Cotsmire, S.; Langland, J.; Kibler, K.V.; Kalman, D.; Upton, J.W.; Mocarski, E.S.; Jacobs, B.L. Inhibition of DAI-dependent necroptosis by the Z-DNA binding domain of the vaccinia virus innate immune evasion protein, E3. Proc. Natl. Acad. Sci. USA 2017, 114, 11506–11511. [Google Scholar] [CrossRef] [Green Version]
  175. Shan, B.; Pan, H.; Najafov, A.; Yuan, J. Necroptosis in development and diseases. Genes Dev. 2018, 32, 327–340. [Google Scholar] [CrossRef]
  176. Liang, Y.X.; Wang, N.N.; Zhang, Z.Y.; Juan, Z.D.; Zhang, C. Necrostatin-1 Ameliorates Peripheral Nerve Injury-Induced Neuropathic Pain by Inhibiting the RIP1/RIP3 Pathway. Front. Cell. Neurosci. 2019, 13, 211. [Google Scholar] [CrossRef]
  177. Ma, D.; Zhao, S.; Liu, X.; Li, Z.; Li, H.; Liu, J.; Cao, J.; Wang, X. RIP3/MLKL pathway-regulated necroptosis: A new mechanism of paclitaxel-induced peripheral neuropathy. J. Biochem. Mol. Toxicol. 2021, 35, e22834. [Google Scholar] [CrossRef]
  178. Fang, P.; Sun, G.Q.; Wang, J.Y. RIP3-mediated necroptosis increases neuropathic pain via microglia activation: Necrostatin-1 has therapeutic potential. FEBS Open Bio 2021, 11, 2858–2865. [Google Scholar] [CrossRef]
  179. Lagana, A.S.; La Rosa, V.L.; Rapisarda, A.M.C.; Valenti, G.; Sapia, F.; Chiofalo, B.; Rossetti, D.; Ban Frangez, H.; Vrtacnik Bokal, E.; Vitale, S.G. Anxiety and depression in patients with endometriosis: Impact and management challenges. Int. J. Womens Health 2017, 9, 323–330. [Google Scholar] [CrossRef] [Green Version]
  180. Hampton, S.N.; Nakonezny, P.A.; Richard, H.M.; Wells, J.E. Pain catastrophizing, anxiety, and depression in hip pathology. Bone Joint J 2019, 101-B, 800–807. [Google Scholar] [CrossRef]
  181. Blackburn-Munro, G.; Blackburn-Munro, R.E. Chronic pain, chronic stress and depression: Coincidence or consequence? J. Neuroendocrinol. 2001, 13, 1009–1023. [Google Scholar] [CrossRef]
  182. Boersma, K.; Sodermark, M.; Hesser, H.; Flink, I.K.; Gerdle, B.; Linton, S.J. Efficacy of a transdiagnostic emotion-focused exposure treatment for chronic pain patients with comorbid anxiety and depression: A randomized controlled trial. Pain 2019, 160, 1708–1718. [Google Scholar] [CrossRef]
  183. Rogers, A.H.; Orr, M.F.; Shepherd, J.M.; Bakhshaie, J.; Ditre, J.W.; Buckner, J.D.; Zvolensky, M.J. Anxiety, depression, and opioid misuse among adults with chronic pain: The role of emotion dysregulation. J. Behav. Med. 2021, 44, 66–73. [Google Scholar] [CrossRef]
  184. Dahl, J.; Ormstad, H.; Aass, H.C.; Malt, U.F.; Bendz, L.T.; Sandvik, L.; Brundin, L.; Andreassen, O.A. The plasma levels of various cytokines are increased during ongoing depression and are reduced to normal levels after recovery. Psychoneuroendocrinology 2014, 45, 77–86. [Google Scholar] [CrossRef]
  185. Hayley, S.; Hakim, A.M.; Albert, P.R. Depression, dementia and immune dysregulation. Brain 2021, 144, 746–760. [Google Scholar] [CrossRef]
  186. Biggs, J.E.; Lu, V.B.; Stebbing, M.J.; Balasubramanyan, S.; Smith, P.A. Is BDNF sufficient for information transfer between microglia and dorsal horn neurons during the onset of central sensitization? Mol. Pain 2010, 6, 1744–8069. [Google Scholar] [CrossRef] [Green Version]
  187. Rana, T.; Behl, T.; Sehgal, A.; Srivastava, P.; Bungau, S. Unfolding the Role of BDNF as a Biomarker for Treatment of Depression. J. Mol. Neurosci. 2021, 71, 2008–2021. [Google Scholar] [CrossRef]
  188. Rainville, P.; Duncan, G.H.; Price, D.D.; Carrier, B.; Bushnell, M.C. Pain affect encoded in human anterior cingulate but not somatosensory cortex. Science 1997, 277, 968–971. [Google Scholar] [CrossRef] [Green Version]
  189. Li, X.Y.; Ko, H.G.; Chen, T.; Descalzi, G.; Koga, K.; Wang, H.; Kim, S.S.; Shang, Y.; Kwak, C.; Park, S.W.; et al. Alleviating neuropathic pain hypersensitivity by inhibiting PKMzeta in the anterior cingulate cortex. Science 2010, 330, 1400–1404. [Google Scholar] [CrossRef]
  190. Xiao, X.; Ding, M.; Zhang, Y.Q. Role of the Anterior Cingulate Cortex in Translational Pain Research. Neurosci. Bull. 2021, 37, 405–422. [Google Scholar] [CrossRef]
  191. Lee, J.A.; Miao, Z.; Chen, Q.Y.; Li, X.H.; Zhuo, M. Multiple synaptic connections into a single cortical pyramidal cell or interneuron in the anterior cingulate cortex of adult mice. Mol. Brain 2021, 14, 88. [Google Scholar] [CrossRef]
  192. Li, Z.Z.; Han, W.J.; Sun, Z.C.; Chen, Y.; Sun, J.Y.; Cai, G.H.; Liu, W.N.; Wang, T.Z.; Xie, Y.D.; Mao, H.H.; et al. Extracellular matrix protein laminin beta1 regulates pain sensitivity and anxiodepression-like behaviors in mice. J. Clin. Investig. 2021, 131, e146323. [Google Scholar] [CrossRef]
  193. Song, Y.; Yao, M.; Kemprecos, H.; Byrne, A.; Xiao, Z.; Zhang, Q.; Singh, A.; Wang, J.; Chen, Z.S. Predictive coding models for pain perception. J. Comput. Neurosci. 2021, 49, 107–127. [Google Scholar] [CrossRef]
  194. Barthas, F.; Humo, M.; Gilsbach, R.; Waltisperger, E.; Karatas, M.; Leman, S.; Hein, L.; Belzung, C.; Boutillier, A.L.; Barrot, M.; et al. Cingulate Overexpression of Mitogen-Activated Protein Kinase Phosphatase-1 as a Key Factor for Depression. Biol. Psychiatry 2017, 82, 370–379. [Google Scholar] [CrossRef] [Green Version]
  195. Barthas, F.; Sellmeijer, J.; Hugel, S.; Waltisperger, E.; Barrot, M.; Yalcin, I. The anterior cingulate cortex is a critical hub for pain-induced depression. Biol. Psychiatry 2015, 77, 236–245. [Google Scholar] [CrossRef]
  196. Su, D.J.; Li, L.F.; Wang, S.Y.; Yang, Q.; Wu, Y.J.; Zhao, M.G.; Yang, L. Pra-C exerts analgesic effect through inhibiting microglial activation in anterior cingulate cortex in complete Freund’s adjuvant-induced mouse model. Mol. Pain 2021, 17, 1744806921990934. [Google Scholar] [CrossRef]
  197. Sun, T.; Wang, J.; Li, X.; Li, Y.J.; Feng, D.; Shi, W.L.; Zhao, M.G.; Wang, J.B.; Wu, Y.M. Gastrodin relieved complete Freund’s adjuvant-induced spontaneous pain by inhibiting inflammatory response. Int. Immunopharmacol. 2016, 41, 66–73. [Google Scholar] [CrossRef]
  198. Zhou, X.; Huang, Z.; Zhang, J.; Chen, J.L.; Yao, P.W.; Mai, C.L.; Mai, J.Z.; Zhang, H.; Liu, X.G. Chronic Oral Administration of Magnesium-L-Threonate Prevents Oxaliplatin-Induced Memory and Emotional Deficits by Normalization of TNF-alpha/NF-kappaB Signaling in Rats. Neurosci. Bull. 2021, 37, 55–69. [Google Scholar] [CrossRef]
  199. Cotter, D.; Mackay, D.; Landau, S.; Kerwin, R.; Everall, I. Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Arch. Gen. Psychiatry 2001, 58, 545–553. [Google Scholar] [CrossRef] [Green Version]
  200. Cotter, D.; Mackay, D.; Chana, G.; Beasley, C.; Landau, S.; Everall, I.P. Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder. Cereb. Cortex 2002, 12, 386–394. [Google Scholar] [CrossRef]
  201. Deng, X.X.; Li, S.S.; Sun, F.Y. Necrostatin-1 Prevents Necroptosis in Brains after Ischemic Stroke via Inhibition of RIPK1-Mediated RIPK3/MLKL Signaling. Aging Dis. 2019, 10, 807–817. [Google Scholar] [CrossRef] [Green Version]
  202. Ni, Y.; Gu, W.W.; Liu, Z.H.; Zhu, Y.M.; Rong, J.G.; Kent, T.A.; Li, M.; Qiao, S.G.; An, J.Z.; Zhang, H.L. RIP1K Contributes to Neuronal and Astrocytic Cell Death in Ischemic Stroke via Activating Autophagic-lysosomal Pathway. Neuroscience 2018, 371, 60–74. [Google Scholar] [CrossRef]
  203. Cao, H.; Zuo, C.; Huang, Y.; Zhu, L.; Zhao, J.; Yang, Y.; Jiang, Y.; Wang, F. Hippocampal proteomic analysis reveals activation of necroptosis and ferroptosis in a mouse model of chronic unpredictable mild stress-induced depression. Behav. Brain Res. 2021, 407, 113261. [Google Scholar] [CrossRef]
  204. Yang, R.; Hu, K.; Chen, J.; Zhu, S.; Li, L.; Lu, H.; Li, P.; Dong, R. Necrostatin-1 protects hippocampal neurons against ischemia/reperfusion injury via the RIP3/DAXX signaling pathway in rats. Neurosci. Lett. 2017, 651, 207–215. [Google Scholar] [CrossRef]
  205. Sakry, D.; Neitz, A.; Singh, J.; Frischknecht, R.; Marongiu, D.; Biname, F.; Perera, S.S.; Endres, K.; Lutz, B.; Radyushkin, K.; et al. Oligodendrocyte precursor cells modulate the neuronal network by activity-dependent ectodomain cleavage of glial NG2. PLoS Biol. 2014, 12, e1001993. [Google Scholar] [CrossRef]
  206. Birey, F.; Kloc, M.; Chavali, M.; Hussein, I.; Wilson, M.; Christoffel, D.J.; Chen, T.; Frohman, M.A.; Robinson, J.K.; Russo, S.J.; et al. Genetic and Stress-Induced Loss of NG2 Glia Triggers Emergence of Depressive-like Behaviors through Reduced Secretion of FGF2. Neuron 2015, 88, 941–956. [Google Scholar] [CrossRef] [Green Version]
  207. Tkachev, D.; Mimmack, M.L.; Ryan, M.M.; Wayland, M.; Freeman, T.; Jones, P.B.; Starkey, M.; Webster, M.J.; Yolken, R.H.; Bahn, S. Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 2003, 362, 798–805. [Google Scholar] [CrossRef]
  208. Atmaca, M.; Onalan, E.; Yildirim, H.; Yuce, H.; Koc, M.; Korkmaz, S. The association of myelin oligodendrocyte glycoprotein gene and white matter volume in obsessive-compulsive disorder. J. Affect. Disord. 2010, 124, 309–313. [Google Scholar] [CrossRef]
  209. Stewart, S.E.; Platko, J.; Fagerness, J.; Birns, J.; Jenike, E.; Smoller, J.W.; Perlis, R.; Leboyer, M.; Delorme, R.; Chabane, N.; et al. A genetic family-based association study of OLIG2 in obsessive-compulsive disorder. Arch. Gen. Psychiatry 2007, 64, 209–214. [Google Scholar] [CrossRef] [Green Version]
  210. Dwork, A.J.; Mancevski, B.; Rosoklija, G. White matter and cognitive function in schizophrenia. Int. J. Neuropsychopharmacol. 2007, 10, 513–536. [Google Scholar] [CrossRef]
  211. Mechawar, N.; Savitz, J. Neuropathology of mood disorders: Do we see the stigmata of inflammation? Transl. Psychiatry 2016, 6, e946. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  212. McGuigan, C.; Hutchinson, M. Unrecognised symptoms of depression in a community-based population with multiple sclerosis. J. Neurol. 2006, 253, 219–223. [Google Scholar] [CrossRef] [PubMed]
  213. Enache, D.; Pariante, C.M.; Mondelli, V. Markers of central inflammation in major depressive disorder: A systematic review and meta-analysis of studies examining cerebrospinal fluid, positron emission tomography and post-mortem brain tissue. Brain Behav. Immun. 2019, 81, 24–40. [Google Scholar] [CrossRef] [PubMed]
  214. Sun, Y.; Chen, X.; Ou, Z.; Wang, Y.; Chen, W.; Zhao, T.; Liu, C.; Chen, Y. Dysmyelination by Oligodendrocyte-Specific Ablation of Ninj2 Contributes to Depressive-Like Behaviors. Adv. Sci. 2022, 9, e2103065. [Google Scholar] [CrossRef]
  215. Dong, H.S.; Han, C.; Jeon, S.W.; Yoon, S.; Jeong, H.G.; Huh, Y.J.; Pae, C.U.; Patkar, A.A.; Steffens, D.C. Characteristics of neurocognitive functions in mild cognitive impairment with depression. Int. Psychogeriatr. 2016, 28, 1181–1190. [Google Scholar] [CrossRef] [Green Version]
  216. Czeh, B.; Lucassen, P.J. What causes the hippocampal volume decrease in depression? Are neurogenesis, glial changes and apoptosis implicated? Eur. Arch Psychiatry Clin. Neurosci. 2007, 257, 250–260. [Google Scholar] [CrossRef]
  217. Khera, T.; Rangasamy, V. Cognition and Pain: A Review. Front. Psychol. 2021, 12, 1819. [Google Scholar] [CrossRef]
  218. Moriarty, O.; McGuire, B.E.; Finn, D.P. The effect of pain on cognitive function: A review of clinical and preclinical research. Prog. Neurobiol. 2011, 93, 385–404. [Google Scholar] [CrossRef] [Green Version]
  219. Mutso, A.A.; Radzicki, D.; Baliki, M.N.; Huang, L.; Banisadr, G.; Centeno, M.V.; Radulovic, J.; Martina, M.; Miller, R.J.; Apkarian, A.V. Abnormalities in hippocampal functioning with persistent pain. J. Neurosci. 2012, 32, 5747–5756. [Google Scholar] [CrossRef] [Green Version]
  220. Mao, C.P.; Bai, Z.L.; Zhang, X.N.; Zhang, Q.J.; Zhang, L. Abnormal Subcortical Brain Morphology in Patients with Knee Osteoarthritis: A Cross-sectional Study. Front. Aging Neurosci. 2016, 8, 3. [Google Scholar] [CrossRef] [Green Version]
  221. Oosterman, J.M.; Derksen, L.C.; van Wijck, A.J.; Veldhuijzen, D.S.; Kessels, R.P. Memory functions in chronic pain: Examining contributions of attention and age to test performance. Clin. J. Pain 2011, 27, 70–75. [Google Scholar] [CrossRef] [PubMed]
  222. Hart, R.P.; Martelli, M.F.; Zasler, N.D. Chronic pain and neuropsychological functioning. Neuropsychol. Rev. 2000, 10, 131–149. [Google Scholar] [CrossRef] [PubMed]
  223. Phelps, C.E.; Navratilova, E.; Porreca, F. Chronic Pain Produces Reversible Memory Deficits That Depend on Task Difficulty in Rats. J. Pain 2021, 22, 1467–1476. [Google Scholar] [CrossRef] [PubMed]
  224. Zhong, L.; Gerges, N.Z. Neurogranin Regulates Metaplasticity. Front. Mol. Neurosci. 2019, 12, 322. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  225. Bin Ibrahim, M.Z.; Benoy, A.; Sajikumar, S. Long-term plasticity in the hippocampus: Maintaining within and ‘tagging’ between synapses. FEBS J. 2022, 289, 2176–2201. [Google Scholar] [CrossRef]
  226. Tyrtyshnaia, A.A.; Manzhulo, I.V.; Konovalova, S.P.; Zagliadkina, A.A. Neuropathic Pain Causes a Decrease in the Dendritic Tree Complexity of Hippocampal CA3 Pyramidal Neurons. Cells Tissues Organs 2019, 208, 89–100. [Google Scholar] [CrossRef]
  227. Liu, Y.; Zhou, L.J.; Wang, J.; Li, D.; Ren, W.J.; Peng, J.; Wei, X.; Xu, T.; Xin, W.J.; Pang, R.P.; et al. TNF-alpha Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury. J. Neurosci. 2017, 37, 871–881. [Google Scholar] [CrossRef] [Green Version]
  228. Ren, W.J.; Liu, Y.; Zhou, L.J.; Li, W.; Zhong, Y.; Pang, R.P.; Xin, W.J.; Wei, X.H.; Wang, J.; Zhu, H.Q.; et al. Peripheral nerve injury leads to working memory deficits and dysfunction of the hippocampus by upregulation of TNF-alpha in rodents. Neuropsychopharmacology 2011, 36, 979–992. [Google Scholar] [CrossRef] [Green Version]
  229. Xu, T.; Li, D.; Zhou, X.; Ouyang, H.D.; Zhou, L.J.; Zhou, H.; Zhang, H.M.; Wei, X.H.; Liu, G.; Liu, X.G. Oral Application of Magnesium-L-Threonate Attenuates Vincristine-induced Allodynia and Hyperalgesia by Normalization of Tumor Necrosis Factor-alpha/Nuclear Factor-kappaB Signaling. Anesthesiology 2017, 126, 1151–1168. [Google Scholar] [CrossRef]
  230. Saffarpour, S.; Janzadeh, A.; Rahimi, B.; Ramezani, F.; Nasirinezhad, F. Chronic nanocurcumin treatment ameliorates pain-related behavior, improves spatial memory, and reduces hippocampal levels of IL-1beta and TNFalpha in the chronic constriction injury model of neuropathic pain. Psychopharmacology 2021, 238, 877–886. [Google Scholar] [CrossRef]
  231. Liu, S.; Wang, X.; Li, Y.; Xu, L.; Yu, X.; Ge, L.; Li, J.; Zhu, Y.; He, S. Necroptosis mediates TNF-induced toxicity of hippocampal neurons. Biomed. Res. Int. 2014, 2014, 290182. [Google Scholar] [CrossRef] [Green Version]
  232. Telegina, D.V.; Suvorov, G.K.; Kozhevnikova, O.S.; Kolosova, N.G. Mechanisms of Neuronal Death in the Cerebral Cortex during Aging and Development of Alzheimer’s Disease-Like Pathology in Rats. Int. J. Mol. Sci. 2019, 20, 5632. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  233. Chan, H.H.; Koh, R.Y.; Lim, C.L.; Leong, C.O. Receptor-Interacting Protein Kinase 1 (RIPK1) as a Potential Therapeutic Target: An Overview of Its Possible Role in the Pathogenesis of Alzheimer’s Disease. Curr. Alzheimer Res. 2019, 16, 907–918. [Google Scholar] [CrossRef] [PubMed]
  234. Jia, R.; Jia, N.; Yang, F.; Liu, Z.; Li, R.; Jiang, Y.; Zhao, J.; Wang, L.; Zhang, S.; Zhang, Z.; et al. Hydrogen Alleviates Necroptosis and Cognitive Deficits in Lithium-Pilocarpine Model of Status Epilepticus. Cell Mol. Neurobiol. 2019, 39, 857–869. [Google Scholar] [CrossRef] [PubMed]
  235. Motawi, T.M.K.; Abdel-Nasser, Z.M.; Shahin, N.N. Ameliorative Effect of Necrosulfonamide in a Rat Model of Alzheimer’s Disease: Targeting Mixed Lineage Kinase Domain-like Protein-Mediated Necroptosis. ACS Chem. Neurosci. 2020, 11, 3386–3397. [Google Scholar] [CrossRef]
  236. Nasseri, B.; Zareian, P.; Alizade, H. Apelin attenuates streptozotocin-induced learning and memory impairment by modulating necroptosis signaling pathway. Int. Immunopharmacol. 2020, 84, 106546. [Google Scholar] [CrossRef]
  237. Colucci, M.; Stefanucci, A.; Mollica, A.; Aloisi, A.M.; Maione, F.; Pieretti, S. New Insights on Formyl Peptide Receptor Type 2 Involvement in Nociceptive Processes in the Spinal Cord. Life 2022, 12, 500. [Google Scholar] [CrossRef]
Ijms 23 07191 g001 550
Figure 1. Tumor necrosis factor-alpha (TNF-α)/TNF receptor 1 (TNFR1)-mediated inflammatory response and cell death pathways. The binding of TNF-α to TNFR1 triggers inflammatory responses, apoptosis and necroptosis. Ubiquitination of receptor interacting protein kinase 1 (RIPK1) promotes cell survival and induces an inflammatory response by activating the NF-κB, p38 MAPK, JNK and ERK signalling pathways. If caspase-8 is present in cells, deubiquitination of RIPK1 results in the formation of either complex IIa or complex IIb, leading to RIPK1-independent apoptosis (RIA) or RIPK1-dependent apoptosis (RDA), respectively. If caspase-8 is absent, necroptosis is initiated, in which RIPk1, receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) protein play a key role.
Figure 1. Tumor necrosis factor-alpha (TNF-α)/TNF receptor 1 (TNFR1)-mediated inflammatory response and cell death pathways. The binding of TNF-α to TNFR1 triggers inflammatory responses, apoptosis and necroptosis. Ubiquitination of receptor interacting protein kinase 1 (RIPK1) promotes cell survival and induces an inflammatory response by activating the NF-κB, p38 MAPK, JNK and ERK signalling pathways. If caspase-8 is present in cells, deubiquitination of RIPK1 results in the formation of either complex IIa or complex IIb, leading to RIPK1-independent apoptosis (RIA) or RIPK1-dependent apoptosis (RDA), respectively. If caspase-8 is absent, necroptosis is initiated, in which RIPk1, receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) protein play a key role.
Ijms 23 07191 g001
Ijms 23 07191 g002 550
Figure 2. Potential mechanisms underlying peripheral and central sensitization via TNF-α or the TNF-α–necroptosis pathway in neuropathic pain. TNF-α regulates voltage-gated sodium channels (VGSCs) to sensitize primary afferents in the peripheral nervous system, affects excitatory and inhibitory synaptic transmissions in central nervous system (CNS), and evokes positive feedback between TNF-α and microglial activation to induce neuroinflammation, thus facilitating pain transmission, adverse pain-associated emotional reactions and cognitive deficits. TNF-α-triggered necroptosis in the dorsal root ganglia (DRG), spinal cord and supraspinal region may be one of the key factors for inducing neuroimmune responses in neuropathic pain.
Figure 2. Potential mechanisms underlying peripheral and central sensitization via TNF-α or the TNF-α–necroptosis pathway in neuropathic pain. TNF-α regulates voltage-gated sodium channels (VGSCs) to sensitize primary afferents in the peripheral nervous system, affects excitatory and inhibitory synaptic transmissions in central nervous system (CNS), and evokes positive feedback between TNF-α and microglial activation to induce neuroinflammation, thus facilitating pain transmission, adverse pain-associated emotional reactions and cognitive deficits. TNF-α-triggered necroptosis in the dorsal root ganglia (DRG), spinal cord and supraspinal region may be one of the key factors for inducing neuroimmune responses in neuropathic pain.
Ijms 23 07191 g002
Ijms 23 07191 g003 550
Figure 3. Global trends in the publication of necroptosis-related articles in the field of neuroscience analyzed via bibliometric analysis. (A) The number of articles published worldwide shows a steady upward trend. (B) The key nodes of necroptosis research [65,141,142,143,144,145].
Figure 3. Global trends in the publication of necroptosis-related articles in the field of neuroscience analyzed via bibliometric analysis. (A) The number of articles published worldwide shows a steady upward trend. (B) The key nodes of necroptosis research [65,141,142,143,144,145].
Ijms 23 07191 g003
Ijms 23 07191 g004 550
Figure 4. Co-occurrence network of keywords in necroptosis research established using the VOSviewer software. Four categories of necroptosis-related keywords are shown in red, blue, green and yellow. The red clusters are largest, and ‘necroptosis’ constitutes the largest node. Keywords associated with neuroinflammation and neurodegeneration such as ‘inflammation’, ‘oxidative stress’, ‘activation’ and ‘neurodegeneration’ are also mentioned.
Figure 4. Co-occurrence network of keywords in necroptosis research established using the VOSviewer software. Four categories of necroptosis-related keywords are shown in red, blue, green and yellow. The red clusters are largest, and ‘necroptosis’ constitutes the largest node. Keywords associated with neuroinflammation and neurodegeneration such as ‘inflammation’, ‘oxidative stress’, ‘activation’ and ‘neurodegeneration’ are also mentioned.
Ijms 23 07191 g004
Table
Table 1. Top 10 journals with the highest co-citations in articles reported on necroptosis in the field of neuroscience.
Table 1. Top 10 journals with the highest co-citations in articles reported on necroptosis in the field of neuroscience.
RankPopular JournalsCo-Citations (n)IF(2021)Research Directions
1Cell34141.584/Q1Cell biology/stem cells
2J biol chem3105.157/Q2Signal transduction
3J neurosci2756.167/Q1Neuroscience/electrophysiology
4P natlacad sci usa27411.205/Q1Biology/physics
5Cell death differ25615.828/Q1Molecular biology/cell differentiation
6Nature24449.962/Q1Life sciences/natural science
7J neurochem2065.372/Q1Neuroinflammation/microglia
8Brain res1873.252/Q3Neuroscience/neuroprotection
9Stroke1817.914/Q1Stroke/cardio cerebrovascular diseases
10Science16947.728/Q1Catalysis/inheritance
Table
Table 2. Top 10 necroptosis-related articles with the highest co-citations in the field of neuroscience.
Table 2. Top 10 necroptosis-related articles with the highest co-citations in the field of neuroscience.
RankSourceCitations (n)Main ResultsResearch DirectionsRef.
1Nat Chem Biol74Identification of necroptosis and its inhibitor Nec-1New pathway of cell death[65]
2Nat Chem Biol48Necrostatinsarea family offirst-in-class inhibitors of RIP1 kinase, the key upstream kinase involved in the activation of necroptosisInhibition of necroptosis and its mechanism[144]
3Nat Rev Mol Cell Biol43Necroptosis can occur in a regulated mannerMolecular mechanisms of necroptosis[151]
4Cell42MLKL is a key mediator of necroptosis signalling downstream of RIP3 kinaseMolecular mechanisms of necroptosis[152]
5Cell32RIP3 controls programmed necroptosis by initiating the pronecrotic kinase cascadeMolecular mechanisms of necroptosis[153]
6Science29RIP3 is a molecular switch between TNF-induced apoptosis and necrosis and is required for RIP1-mediated necrosisMolecular mechanisms of necroptosis[154]
7Cell29RIP3 as a determinant for cellular necrosis is recruited to RIPK1 to form a necrosis-inducing complexMolecular mechanisms of necroptosis[155]
8Cell rep28Necroptosis is involved in multiple sclerosis (MS), and RIPK1 may represent a therapeutic strategyRole of necroptosis in MS[156]
9Nature28A review of the regulatory mechanisms of necroptosis and its potential role in inflammation and diseasesMolecular mechanisms of necroptosis and its role in inflammation[61]
10Nat Immunol.24RIP is required for caspase-independent necrotic death induced by Pas, TNF and TRAILMolecular mechanisms of cell death[54]
Table
Table 3. Top 10 necroptosis-related articles with the highest citations in the field of neuroscience.
Table 3. Top 10 necroptosis-related articles with the highest citations in the field of neuroscience.
RankSourceCitations (n)Main ResultsResearch DirectionsRef.
1Neuron244Necroptosis drives motor neuron death in models of both sporadic and familial amyotrophic lateral sclerosis (ALS)Role of necroptosis in ALS[157]
2Nat Rev Neurosci197Review of necroptosis in neurological diseasesRole of necroptosis in neurological diseases[158]
3Nat Neurosci152Genes regulated by RIPK1 overlap with multiple transcriptomic signatures of Alzheimer’s disease (AD) Role of necroptosis in AD[159]
4Prog Neurobiol.148Review of the regulation of autophagy in neurons, glia, and brain microvascular cells in response to ischemia stressCrosstalk between autophagy, necroptosis and apoptosis[160]
5J Pineal Res136Melatonin inhibits the Ripk3–PGAM5–CypD–mPTP cascade and hence reduces necroptosisRole of necroptosis in ischaemia–reperfusion injury[161]
6J Neuroinflammation131Review of the molecular mechanisms of necroptosis and its relevance to diseasesThe molecular mechanisms of necroptosis and its role in disease[147]
7Front Neurosci131Review of targeting Nrf2 to suppress ferroptosis and mitochondrial dysfunction in neurodegenerationNeuroprotective signalling pathways[162]
8Adv Exp Med Biol92Review stating that the biochemical pathways causing programmed neurodegeneration, instead of neuronal death per se, are responsible for epileptogenesisReprogramming of neuronal death pathways in epileptogenesis[163]
9J Neurosci88The axodestructive factor Sarm1 is required for mitochondrial depolarisation-induced axon degeneration and cell deathA novel form of programmed cell destruction called sarmoptosis[164]
10Nat Neurosci87Efficient remyelination requires the death of microglia followed by their repopulation to a pro-regenerative stateRole of microglia in white matter regeneration[53]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Duan, Y.-W.; Chen, S.-X.; Li, Q.-Y.; Zang, Y. Neuroimmune Mechanisms Underlying Neuropathic Pain: The Potential Role of TNF-α-Necroptosis Pathway. Int. J. Mol. Sci. 2022, 23, 7191. https://doi.org/10.3390/ijms23137191

AMA Style

Duan Y-W, Chen S-X, Li Q-Y, Zang Y. Neuroimmune Mechanisms Underlying Neuropathic Pain: The Potential Role of TNF-α-Necroptosis Pathway. International Journal of Molecular Sciences. 2022; 23(13):7191. https://doi.org/10.3390/ijms23137191

Chicago/Turabian Style

Duan, Yi-Wen, Shao-Xia Chen, Qiao-Yun Li, and Ying Zang. 2022. "Neuroimmune Mechanisms Underlying Neuropathic Pain: The Potential Role of TNF-α-Necroptosis Pathway" International Journal of Molecular Sciences 23, no. 13: 7191. https://doi.org/10.3390/ijms23137191

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop