Neuroimmune Interactions and Pain
Abstract and Keywords
Chronic pain imposes a tremendous burden on the sufferer’s quality of life. Mounting evidence supports a critical role for neuroimmune interactions in the development and maintenance of chronic pain. Nerve injury leads to the activation of glia via sphingosine-1-phosphate, Toll-like receptors, chemokines, neuropeptides, and purinergic receptors. In turn, activated glia influence neuronal activity via interleukin 1β, tumor necrosis factor, brain-derived neurotrophic factor, reactive oxygen species, and excitatory amino acids. Epigenetic mechanisms of neuroimmune communication are also discussed. Investigation of neuroimmune interactions after peripheral nerve injury broadens our understanding of the mechanisms that drive neuropathic pain, and such interactions provide potential therapeutic targets for managing neuropathic pain.
Approximately 11% of adults in the United States have daily chronic pain (Nahin, 2015). Chronic neuropathic pain caused by injury or disease affecting the nervous system greatly reduces quality of life, frequently necessitates a visit to the doctor, and is often refractory to treatment (Mu, Weinberg, Moulin, & Clarke, 2017). Research accumulated over decades has demonstrated that neuroimmune interactions play a critical part in the development of neuropathic pain.
Several discoveries have increasingly revealed the role of neuroimmune signaling in pain in animal models. The first was the incidence of pain in the sickness response. The behaviors comprising the sickness response, which also include depression, lethargy, anxiety, and loss of grooming, are adaptive activities that promote recovery from infection and injury. Critically, the sickness response is mediated by cytokine activity in the brain (Kent, Bluthé, Kelley, & Dantzer, 1992), suggesting that pain may similarly be mediated by centrally active cytokines. This was demonstrated by discoveries that elevated levels of peripheral and central cytokines, including interleukin (IL) 1β, induce hyperalgesia (Bianchi, Sacerdote, Ricciardi-Castagnoli, Mantegazza, & Panerai, 1992; Ferreira, Lorenzetti, Bristow, & Poole, 1988; Maier, Wiertelak, Martin, & Watkins, 1993; Watkins et al., 1994).
At a similar point in time, other studies identified a link between glial activation and pain. Primary spinal cord astrocytes were shown to release inflammatory products in vitro in response to substance P, a peptide released by nociceptors (Marriott, Wilkin, Coote, & Wood, 1991; Marriott, Wilkin, & Wood, 1991). In addition, astrocytes were found to be activated after axon damage and nerve transection (Garrison, Dougherty, Kajander, & Carlton, 1991; Graeber & Kreutzberg, 1986; Nolan & Brown, 1989). Collectively, these data suggested that astrocytes may process noxious input. This was confirmed when the astrocyte cell-cycle inhibitor fluorocitrate was used to attenuate inflammatory pain (Meller, Dykstra, Grzybycki, Murphy, & Gebhart, 1994). Finally, activation of microglia after ischemia and seizures also was revealed to be a response of microglia to neuronal activity (DeLeo, Toth, Schubert, Rudolphi, & Kreutzberg, 1987; Shaw, Perry, & Mellanby, 1990). Subsequently, spinal microglia were found to be activated in response to inflammatory and neuropathic pain, and inhibition with minocycline revealed a causal role for microglia in emergent pain behaviors (Colburn, Rickman, & DeLeo, 1999; Raghavendra, Tanga, Rutkowski, & DeLeo, 2003; Winkelstein, Rutkowski, Sweitzer, Pahl, & DeLeo, 2001). The sufficiency of and necessity for microglia in the production of neuropathic pain as shown in these early studies was recently confirmed in studies using designer receptors exclusively activated by designer drugs (DREADDs), which are genetically targeted to microglia and have high selectivity (Grace, Strand, et al., 2016; Grace, Wang, et al., 2018).
These and subsequent discoveries in animals and humans illustrate the importance of the immune system in the development and maintenance of chronic pain (Grace, Hutchinson, Maier, & Watkins, 2014; Ji, Xu, & Gao, 2014). Basic science studies of neuropathic pain have predominantly focused on neuroimmune signaling in the spinal cord; this anatomical site is the focus of this review. First, we describe how nerve injury activates immune cells and glia. Next, we review how such cells promote neuronal activity that induces pain and how anti-inflammatory cytokines resolve pain. We conclude by discussing epigenetic mechanisms that promote neuroimmune signaling. Recognition of the communications between the immune and nervous systems broadens our view of chronic pain and suggests that pain might be relieved by targeting the immune system.
Glia Are Activated in Response to Nerve Injury
Peripheral nerve injury models of neuropathic pain, including spared nerve injury, spinal nerve ligation, chronic constriction injury, and their derivatives (Mogil, 2009), have been used in many studies and reveal crosstalk between neuronal and nonneuronal cells. Microglia and astrocytes are key nonneuronal cells that reside in the central nervous system (CNS). Microglia originate from progenitors derived from the yolk sac and migrate into the brain during early embryonic development; they serve as the tissue-resident macrophages in the CNS (Gomez Perdiguero et al., 2015; Tay, Hagemeyer, & Prinz, 2016). Self-renewal of microglia is highly dynamic in order to maintain a stable population (5‒12% of mouse brain glia; 0.5–16.6% in human brain) throughout life (Askew et al., 2017). Microglial function, such as trophic support for neurons, debris clearance, and synapse remodeling, is essential for maintaining brain homeostasis and the innate immune response. In addition, microglia are reported to participate in neuronal circuit formation and plasticity during embryonic development (Vainchtein et al., 2018).
Astrocytes are the largest and most abundant (approximately 30%) glial cells in the mammalian CNS (Liddelow & Barres, 2017). Astrocytes are subdivided into two groups, protoplasmic astrocytes in the gray matter and fibrous astrocytes in the white matter (Kettenmann & Verkhratsky, 2008). The protoplasmic astrocytes enwrap the synapses and can also directly connect with blood vessels or meninges through their star-shape terminal structure, the endfoot, which forms the glia limitans. The glia limitans is involved in maintaining blood–brain barrier integrity (Sofroniew, 2015). Importantly, protoplasmic astrocytes account for the development and maintenance of neuropathic pain in the spinal cord, given that they are activated after peripheral nerve injury and correlated with painful sensitivity (Chen et al., 2014; Garrison et al., 1991; Lu et al., 2014, p. 6). Fibrous astrocytes connect with myelinated axonal tracts, such as the corpus callosum and the nodes of Ranvier (Allen & Eroglu, 2017).
Thus, astrocytes are crucial cellular compartments that provide metabolic and trophic support to neurons (Allen & Eroglu, 2017). Further, astrocytes can be activated by inflammation and can trigger adaptive and innate immune responses that release cytokines and chemokines and present antigens (Jensen, Massie, & De Keyser, 2013), which is critical to pain development (Grace et al., 2014). Microglia and astrocytes are recruited after peripheral nerve injury, leading to increased expression of surface receptors, proliferation, morphological changes, and release of pro-inflammatory mediators. The recruiting signals are released by injured neurons, which activate a range of receptors expressed by glia (Figure 1).
Sphingosine-1-phosphate (S1P), the sphingolipid metabolite, is a bioactive lipid mediator that serves as a signaling transductor (Healy & Antel, 2016). S1P and S1P receptor 1 (S1PR1) are involved in neuropathic pain (Salvemini, Doyle, Kress, & Nicol, 2013). S1PR1 is primarily expressed in astrocytes, and inhibition of S1PR1 efficiently attenuates carrageenan-induced thermal hyperalgesia (Finley et al., 2013; Nishimura, Akiyama, Irei, Hamazaki, & Sadahira, 2010). S1P and S1PR1 also take part in bortezomib-induced neuropathic pain, and knockout of S1PR1 in astrocytes prevents the development of neuropathic pain in mice (Stockstill et al., 2018).
Toll-like receptors (TLRs) are a class of pattern-recognition receptors that recognize microbes and induce inflammatory responses. TLRs have common extracellular leucine-rich repeats that allow binding of damage-associated molecular patterns (DAMPs) during tissue damage. After activation, TLRs trigger mitogen-activated protein kinases (extracellular signal–regulated kinase, p38, and c-Jun N-terminal kinase [JNK]) and nuclear factor κB cascades to produce cytokines (see our recent review about TLRs; Lacagnina, Watkins, & Grace, 2018). Nerve injury causes cell damage and cell death, which produces DAMPs such as high-mobility group box protein 1 (HMGB1), heat-shock proteins (HSPs), and histone proteins, as well as nucleic acids (Lacagnina et al., 2018). These noxious endogenous ligands bind TLRs on the microglial cell membrane and serve a functional role in activating microglia and inducing neuropathic pain (Liu, Gao, & Ji, 2012).
High-mobility group box protein 1 is a nonhistone protein that consists of 215 amino acids and acts as a chaperone protein in the nucleus for DNA replication and repair under physiological conditions (Braza, Brouard, Chadban, & Goldstein, 2016; Lotze & Tracey, 2005). In contrast, extracellular HMGB1 secreted from immune cells or released from injured cells functions like a cytokine to induce inflammation (Wan et al., 2016). Nerve injury induces HMGB1 translocation from the nucleus to the cytoplasm; depolarization of cultured neurons induces HMGB1 release in vitro (Feldman, Due, Ripsch, Khanna, & White, 2012). The increased neuronal HMGB1 leads to the activation of microglia in the spinal dorsal horn through its receptors TLR4 and receptor for advanced glycation end products (RAGE), whereas blocking HMGB1 by pharmacological molecules or antibodies reduces microglial activation and neuropathic pain (Grace, Strand, et al., 2018; Kato, Agalave, & Svensson, 2016; Kato & Svensson, 2015; Nakamura et al., 2013; Shibasaki et al., 2010). In addition, HSP90 may be involved in microglia activation and pain establishment after nerve injury because studies showed that inhibition of HSP90 attenuated neuropathic pain and decreased neuroinflammation (Grace, Strand, et al., 2018; Hutchinson et al., 2009; Lei et al., 2017). TLR4-mediated microglial activation and neuropathic pain may be sex dependent, given that reversal of allodynia by TLR4 inhibition occurs only in male mice (Sorge et al., 2011, 2015; Stokes, Cheung, Eddinger, Corr, & Yaksh, 2013). Besides TLR4, TLR2 and TLR3 also play essential roles in mediating microglia activation and pain development, as genetic ablation or pharmacological inhibition of TLR2, TLR3, and TLR4 can prevent neuronal inflammation and neuropathic pain (Lacagnina et al., 2018; Liu et al., 2012).
Recent studies suggest that chemokine (C-C motif) ligand (CCL)2, CCL7, CCL12, and colony-stimulating factor (CSF) 1 are increased in injured neurons, and that this is dependent on the Sarm1/Myd88-Jnk-c-Jun pathway, as c-Jun can directly bind regulatory regions of CCL2, CCL7, and CSF1 genes to promote their expression, and genetic ablation of Sarm1/Myd88, Jnk, or c-Jun blocks the production of CCL2, CCL7, and CSF1 after neuronal injury (Wang et al., 2018). In addition, deletion or knockdown of Sarm1/Myd88, Jnk, or c-Jun reduces neuropathic pain (Liu et al., 2014, 2016; Manassero et al., 2012; Son et al., 2007; Stokes et al., 2013).
Colony-stimulating factor 1 participates in activating spinal microglia after peripheral nerve injury. CSF1 is rapidly induced in dorsal root ganglia (DRG) neurons within 1 day of nerve injury and lasts for weeks thereafter (Guan et al., 2016). CSF1 is transported from the DRG to the spinal cord and released to activate CSF1 receptor, which is specifically expressed by microglia (Guan et al., 2016). Of note, expression of pro-inflammatory mediators by CSF1 is dependent on the membrane adaptor protein DNAX-activating protein of 12 kDa (DAP12), whereas microglial proliferation is DAP12 independent (Guan et al., 2016). Neuronal CSF1 is necessary for neuropathic pain development, given that knockout of CSF1 in DRG neurons prevents the development of allodynia in mice (Guan et al., 2016). CSF1 induction is regulated by the neuronal stress sensor dual leucine zipper kinase (DLK) after nerve injury. DLK knockout mice fail to upregulate CSF1 after nerve injury, and pharmacological or genetic inhibition of DLK reduces mechanical hypersensitivity in mice (Wlaschin et al., 2018). The CSF1-IRS5 (insulin receptor substrates 5)-P2X4 (purinergic receptor P2X 4)-BDNF (brain-derived neurotrophic factor) axis promotes the communication between microglia and neurons. Peripheral nerve injury–induced upregulation of P2X4 in spinal microglia contributes to pain development (Tsuda et al., 2003). Furthermore, P2X4 upregulation is controlled by upregulated transcription factors CSF1 and IRS5 and adenosine triphosphate (ATP) and contributes to the release of BDNF from microglia, which promotes neuronal activity (Inoue & Tsuda, 2018).
Chemokines (CCL2 and CX3CL1) and their receptors are required for mediating microglial activation after nerve injury. CCL2 (also known as monocyte-chemotactic protein (MCP) 1) is 1 of 28 members of the CC subfamily of chemokines and preferentially binds to CCR2, a G protein–coupled receptor. CCL2 and CCR2 contribute to neuropathic pain (Grace et al., 2014), as well as to oxaliplatin-induced mechanical hypersensitivity and bone cancer pain in a murine model (Guo et al., 2016). Nerve injury induced CCL2 and CCR2 in spinal cord microglia, and genetic knockout Ccr2 reduced neuropathic pain and spinal microgliosis in mice (Abbadie et al., 2003; Thacker et al., 2009).
CX3C-chemokine ligand 1 (CX3CL1; also known as fractalkine) is the only member of the CX3C subfamily and is a large cytokine protein (373 amino acids) with an extended mucin-like stalk and a chemokine domain on top. Membrane-anchored CX3CL1 promotes adhesion of leukocytes to activated endothelial cells, whereas a soluble version of CX3CL1 chemoattracts T cells and monocytes (Bazan et al., 1997; Imai et al., 1997). In DRG and spinal cord, CX3CL1 and its receptor CX3C-chemokine receptor 1 (CX3CR1) are expressed in neurons and microglia, respectively (Verge et al., 2004). Neuropathy leads to an increase in gene expression of CX3CR1 but not CX3CL1 (Verge et al., 2004; Zhuang et al., 2007). CX3CL1 may be a secondary signal to microgliosis because CX3CL1 can be cleaved and secreted from DRG and spinal cord through treatment with cathepsin S (a lysosomal cysteine protease) after nerve injury (Clark et al., 2007; Zhuang et al., 2007). Neuropathic pain is abrogated in cx3cr1 knockout mice and is reduced by the spinal administration of a CX3CR-neutralizing antibody in rats (Clark et al., 2007; Zhuang et al., 2007).
CCL7 (also known as MCP3) belongs to the CC chemokine subfamily and attracts monocytes. Nerve injury induces an upregulation of CCL7 in spinal cord astrocytes to sustain neuropathic pain in mice, and intrathecal administration of a CCL7 antibody inhibits nerve injury–induced spinal microglial activation and neuropathic pain (Imai et al., 2013). Further, CCR2, the repressor of CCL7, medicates nerve injury–induced microglial activation, as genetic ablation of CCR2 reduces microglial activity and neuropathic pain (Abbadie et al., 2003; Imai et al., 2013). Evidence suggests that bone marrow stromal cells pretreated with IL-1β have an antinociceptive effect by reducing CCL7 and microglial activity through release of IL-10 (Li et al., 2017).
Neurotransmitters such as substance P may contribute to the activation of microglia and astrocytes under nerve injury. Substance P is an 11-amino-acid neuropeptide that belongs to the tachykinin neuropeptide family. Acting as a neurotransmitter and as a neuromodulator, substance P is synthesized by small-diameter sensory fibers and released into the spinal dorsal horn after intense peripheral stimulation. Neurokinin 1 receptor (NK1R), responding to substance P, is a G protein–coupled receptor expressed in neurons, microglia, and astrocytes (Burmeister et al., 2017; Mashaghi et al., 2016). NK1R is suggested to contribute to the activation of microglia and astrocytes, as inhibitors for NK1R can decrease their activation, and Nk1r knockout mice show more tolerance to mechanical stimuli after nerve injury (Mansikka et al., 2000; Tumati et al., 2012). Importantly, substance P mediates immune cell proliferation and cytokine production (Mashaghi et al., 2016; Sun & Bhatia, 2014). However, the precise function of NK1R in astrocytes and microglia under neuropathic pain needs further characterization.
Adenosine triphosphate also is an important trigger for microglial activation in spinal cord after peripheral nerve injury. The induced expression of purinergic receptors P2X4R in spinal microglia cells contributes to the activation of microglia and the development of tactile allodynia: Intrathecal injection of microglia that have been treated with ATP induces pain sensitivity, whereas P2X4R inhibition with antisense nucleotides or inhibitors suppresses allodynia (Tsuda et al., 2003). In addition, P2X7R, P2Y12R, and P2Y13R have been implicated in neuropathic pain because experiments showed that pharmacologically blocked receptor function and genetic ablation greatly reduced pain (Grace, Strand, et al., 2016; Kobayashi et al., 2008; Sorge et al., 2012; Tozaki-Saitoh et al., 2008). These data provide compelling evidence that ATP receptor activation is crucial to microgliosis and the development of neuropathic pain.
Glial-Derived Mediators Promote Activity in Pain Pathways
As noted, a consequence of activation of nonneuronal cells is the production of bioactive mediators (Figure 1). IL-1β and tumor necrosis factor (TNF, previously known as TNF-α) produced by microglia have an active role in promoting pain establishment and maintenance, as elevated levels of IL-1β and TNF have been shown to induce pain behaviors (Bianchi et al., 1992; Ferreira et al., 1988; Leung & Cahill, 2010; Maier et al., 1993; Wagner & Myers, 1996; Watkins et al., 1994). Receptors for IL-1β (IL-1R1) and TNF (TNFR1) located in neurons are greatly induced after nerve injury (Boka et al., 1994; Viviani et al., 2003; Wei, Guo, Zou, Ren, & Dubner, 2008). The induced TNF and IL-1β modulate excitatory synaptic transmission to promote neuronal excitability. On one hand, TNF and IL-1β increase glutamate release from the presynaptic terminals involved in the activation of N-methyl-d-aspartate (NMDA) receptors and transient receptor potential cation channel subfamily V member 1 (TRPV1) (Park et al., 2011; Yan & Weng, 2013). On the other hand, TNF and IL-1β also directly activate postsynaptic terminals by increasing the traffic of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors to the membrane and the phosphorylation of the NR1 and NR2A or NR2B subunits of the NMDA receptor (Kawasaki, Zhang, Cheng, & Ji, 2008; Stellwagen, Beattie, Seo, & Malenka, 2005; Stellwagen & Malenka, 2006; Viviani et al., 2003; Zhang et al., 2008). Of note, IL-1β, but not TNF, directly decreases inhibitory signaling in the spinal dorsal horn by suppressing both γ-aminobutyric acid (GABA) and glycine currents from interneurons and inhibitory descending projections (Kawasaki et al., 2008).
Brain-derived neurotrophic factor is an important link through microglia to neurons during neuropathic pain. BDNF is a growth factor that acts on neurons of the CNS and the peripheral nervous system, supporting the survival, growth, and differentiation of neurons (Acheson et al., 1995; Huang & Reichardt, 2001). BDNF is dramatically increased in microglia after nerve injury and contributes to neuropathic pain, as preventing BDNF release from microglia using interfering RNA directed against BDNF and its receptor tropomyosin receptor kinase B (TrkB) inhibits allodynia (Coull et al., 2005; Dougherty, Dreyfus, & Black, 2000). In agreement, ablation of TrkB neurons prevents neuropathic pain in mice (Dhandapani et al., 2018). BDNF is also required for the transition from acute pain to chronic pain (Sikandar et al., 2018). GluN2B-NMDA receptors are upregulated and activated by BDNF via Src homology 2 domain–containing protein tyrosine phosphatase 2 (SHP2) phosphorylation after nerve injury in rat spinal cord, and inhibition of SHP2 with small interfering RNA (siRNA) or inhibitor in the spinal dorsal horn suppresses BDNF-induced NMDA activity and pain (Ding et al., 2015). In addition, the phosphorylation and potentiation of NMDA (NR2B) mediated by BDNF after nerve injury is through Src family kinase Fyn, as intrathecally administration of Fyn-peptides blocks BDNF-potentiated NMDA after nerve injury (Chen et al., 2014; Hildebrand et al., 2016; Li et al., 2017). In parallel with the potentiation of excitatory neurons, BDNF also downregulates the potassium chloride cotransporter KCC2 via TrkB receptors, which causes an increase in intracellular Cl− levels and weakens GABAergic inhibition (Chen et al., 2014; Coull et al., 2005, 2003; Keller, Beggs, Salter, & De Koninck, 2007).
Reactive oxygen species (ROS) are produced by microglia after activation and induce neuronal excitability (Block, Zecca, & Hong, 2007; Grace, Gaudet, et al., 2016). Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is the major enzyme that catalyzes the production of superoxide from oxygen. Nerve injury induces NADPH oxidase 2 (Nox2) in microglia and thus accounts for the increased ROS level (Kim et al., 2010). The allodynia developed from nerve injury and increased gene expression of IL-1β and TNF are greatly reversed in nox2 knockout mice, which supports a critical role for microglial Nox2 in pain development (Kim et al., 2010). ROS directly influence neuronal activity by upregulating glutamate release from presynaptic terminals involving TRPV1 and TRPA1, as antagonists of TRPV1 or TRPA1 inhibit the induced frequency of spontaneous excitatory postsynaptic currents by the ROS donor tert-butyl hydroperoxide (Bittar et al., 2017; Nishio et al., 2013). In addition, ROS act to repress inhibitory GABA neurons after nerve injury because the antihyperalgesic effect of phenyl-N-tert-butylnitrone (a ROS scavenger) on mechanical hyperalgesia was attenuated by intrathecally administrating bicuculline [a GABA(A) receptor blocker] (Yowtak et al., 2011).
Excitatory amino acid neurotransmitters, such as D-Serine, released from astrocytes also contribute to neuron excitability and pain (Miraucourt, Peirs, Dallel, & Voisin, 2011). The production of D-Serine and its synthesis enzyme serine racemase (Srr) are both significantly increased in astrocytes in the spinal cord dorsal horn after nerve injury, and elimination of endogenous D-Serine or selective blockade of Srr reduces mechanical allodynia (Moon et al., 2015). D-Serine increased NMDA activity in protein kinase C–dependent phosphorylation of GluN1 (Choi et al., 2017).
Further, glutamate transporter in astrocytes contributes to neuropathic pain. Glutamate transporter 1 (GLT1) is exclusively expressed in the astrocytes and clears the excitatory glutamate from the extracellular space at synapses in the CNS (Danbolt, 2001). GLT1 is greatly reduced in spinal astrocytes 14 days after nerve injury, and overexpression of GLT1 in spinal cord greatly reduced chronic pain (Falnikar, Hala, Poulsen, & Lepore, 2016; Wang et al., 2008).
Epigenetic Aspects of Immunity in Pain
Epigenetics describes the processes that lead to stable changes that occur during development or in response to any other environmental stimuli without DNA sequence mutation (Berger, Kouzarides, Shiekhattar, & Shilatifard, 2009; Dupont, Armant, & Brenner, 2009). Epigenetic regulation includes DNA methylation, histone modification, histone variation, and small RNA activity (Allis & Jenuwein, 2016). High diversity and versatility of the chromatin structure established by epigenetic processes enable cells to easily respond to external stimuli and develop transient or long-lasting changes. Emerging evidence indicates important roles for epigenetic regulation of cytokines after neuropathic pain.
Histone deacetylase 1 (HDAC1) is expressed by astrocytes and microglia in the spinal dorsal horn and is increased after nerve injury. Exercise can reduce HDAC1 in microglia with increased histone H3K9ac and attenuates neuropathic pain in a mouse model (Kami, Taguchi, Tajima, & Senba, 2016). Peripheral nerve injury increased CCL7 gene expression in spinal cord with decreased H3K27me3, which is a repressing histone marker (Imai et al., 2013). However, the enzymatic response to the changes in H3K27me3 is not well addressed in neuropathic pain. Upregulation of CXCL12 induced by the cancer drug antitubulin contributes to pain by increasing synaptic transmission and glutamate release from afferent neurons to the spinal cord. Interestingly, the increase in CXCL12 induced by antitubulin is associated with increased acetylation of histone H4 on the promoter of CXCL12, which is caused by the binding of signal transducer and activator of transcription 3 (STAT3) and p300 (histone acetyltransferase; Dancy & Cole, 2015) to the CXCL12 gene promoter, and treatment with an inhibitor of STAT3 reduces CXCL12 and chemotherapy-induced pain (Xu et al., 2017). Genome-wide chromatin immunoprecipitation sequencing data from spinal microglia in mice demonstrated that nerve injury increased the occupancy of H3K4me1 on the enhancer of many cytokine genes, such as CCL12 and CCL5. In addition, increased H3K4me1 on potential enhancers was associated with increased cytokine gene expression in microglia after nerve injury, suggesting a critical role for epigenetic regulation in cytokine gene expression (Denk, Crow, Didangelos, Lopes, & McMahon, 2016). Histone methyltransferases lysine (K)-specific methyltransferase 2C/D (KMT2C/D, also known as myeloid/lymphoid or mixed-lineageleukemia protein 3/4, MLL3/4) and chromatin remodeling complex are required for the establishment of H3H4me1 (Lee et al., 2013; Local et al., 2018), but their role in neuropathic pain, especially leading to changes in H3K4me1 in microglia, needs further study.
Brain-derived neurotrophic factor can be epigenetically regulated by lysine demethylase 4A (KDM4A, also known as JMJD2A), ten-eleven translocation methylcytosine dioxygenase 1 (Tet1), and microRNA 206 (miR-206). KDM4A, a JmjC histone demethylase that catalyzes the demethylation of di- and trimethylated histone H3 at Lys9 and Lys36 in histone H3 (H3K9me2/3 and H3K36me2/3, respectively), is upregulated and binds to the promoter region of BDNF to promote BDNF expression after nerve injury. Neuronal deletion of KDM4A reduces BDNF, which is increased by nerve injury, and normalizes the pain threshold, which is decreased by nerve injury (Zhou, Wang, Xu, Zhou, & Zhang, 2017). Similar to KDM4A, Tet1, a critical enzyme for DNA demethylation by the conversion of 5-methylcytosine to 5-hydroxymethylcytosine (Wu & Zhang, 2010), is also upregulated and involved in the regulation of BDNF gene expression after nerve injury; knockdown of Tet1 reduces BDNF as well as neuronal excitability and pain (Hsieh et al., 2016). In addition, miR-206, which targets the 3′ untranslated region of BDNF, also is involved in nerve injury–induced neuropathic pain, as overexpression of miR-206 suppresses BDNF, which is increased by nerve injury. miR-206 overexpression also attenuates neuropathic pain (Sun, Zhang, & Li, 2017).
Pain Resolution Through Anti-inflammatory Signaling
Due to the critical role of neuroimmune crosstalk in pain development and maintenance, efficient therapeutic targets are designed to address neuroimmune-mediated molecular interaction.
Interleukin 10 is a powerful anti-inflammatory cytokine that can be used to treat neuropathic pain (Grace et al., 2017; Milligan, Langer, et al., 2005; Milligan, Sloane, et al., 2005; Sloane et al., 2009). IL-10 is produced by glia and immune cells, as well as by neurons. After binding to its tetramerized receptors (two copies of IL-10R1 and IL-10R2), IL-10 leads to the phosphorylation and dimerization of STAT3, which results in the activation of downstream anti-inflammatory genes (King, Balaji, Le, Crombleholme, & Keswani, 2014; Kwilasz, Grace, Serbedzija, Maier, & Watkins, 2015a). The levels of IL-10 in blood, spinal cord, or cerebrospinal fluid tissues are decreased in patients as well as in animal models of neuropathic pain (Backonja, Coe, Muller, & Schell, 2008; Jancalek, Svizenska, Klusakova, & Dubovy, 2011; Uçeyler, Rogausch, Toyka, & Sommer, 2007), and IL-10 gene therapy has been proven to be a powerful strategy to treat neuropathic pain (Kwilasz, Grace, Serbedzija, Maier, & Watkins, 2015b). Strikingly, a single low dose of IL-10 DNA delivered using poly(lactic-co-glycolic-acid) (PLGA) microparticles relieved neuropathic pain for a prolonged period of time (Soderquist et al., 2010), as PLGA has the advantage of protecting the DNA from degradation by extracellular and intracellular enzymes and releasing its package in a slower manner (Abbas, Donovan, & Salem, 2008; Kaneda, 2001; Sebestyén et al., 1998). It is also worth noting that a fusion protein, IL-4, combined with IL-10 shows more efficacy in attenuating carrageenan-induced inflammatory pain than the single IL-4 or IL-10 protein, through reducing the activity of microglia and astrocytes and the expression of TNF, IL-1β, BDNF, and CCL2 (Eijkelkamp et al., 2016). Protectin D1 and the resolvins RvE1 and RvD1, derived from omega-3 polyunsaturated fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) have a neuroprotective role in decreasing neuroinflammation and neuropathic pain without tolerance through reducing microglial activity and glutamate release and inhibiting the production of cytokines, such as CCL2, TNF, and IL-1β (Ji et al., 2014; Xu et al., 2010).
Conclusion and Perspective
Neuronal activities are tightly connected and influenced by their surrounding glia. There are other factors that influence neuroimmunity and neuropathic pain and that warrant additional investigation. Besides epigenetic regulation, age and sex are crucial factors. The population of immune cells infiltrating the DRG after peripheral nerve injury depends on the sex of the animal (Lopes et al., 2017), and microglia may play a greater role in neuropathic pain in male rodents (Mapplebeck, Beggs, & Salter, 2017; Sorge et al., 2015; Taves et al., 2016). The development of neuropathic pain is disrupted in young animals but increases with age (McKelvey, Berta, Old, Ji, & Fitzgerald, 2015). Circadian rhythm also contributes to pain development (Das et al., 2018; Junker & Wirz, 2010; Morioka et al., 2016; Perreau-Lenz, Sanchis-Segura, Leonardi-Essmann, Schneider, & Spanagel, 2010). Because immunity has a circadian rhythm (Curtis, Bellet, Sassone-Corsi, & O’Neill, 2014; Fonken et al., 2015; Zhang et al., 2012), its disruption by neuropathy may exacerbate neuroimmune interactions. This area requires further research.
Imaging studies are beginning to shed light on the role of CNS neuroimmunity in human pain conditions. Positron emission tomography and magnetic resonance imaging of translocator protein TSPO (18 kDa), a putative microglial activation marker, has been introduced to track glial activation in vivo using radioligands such as 11C-PBR28 (Albrecht et al., 2018; Loggia et al., 2015; Paganoni et al., 2018) and [18F]DPA-714 (Lavisse et al., 2015). Radioligand binding is increased in the spinal cord and thalamus of patients with chronic pain, suggestive of glial activation (Albrecht et al., 2018; Loggia et al., 2015). Real-time live imaging in vivo serves as a powerful tool for detecting microglial activation and dynamics in humans. Future studies are required to define the function of TSPO, and radioligands with cell selectivity are required.
Although blocking glial activation helps to reduce neuropathy-induced pain, glial cells have benefits for neuron support, survival, regeneration, blood–brain/spinal cord barrier integrity, and host defense. As bacteria evolve to survive by reducing pain through blocking neuroimmune interaction, so balancing the activity of glia in pain development and neuronal protection and host defense should also be addressed in future work.
Glia-to-neuron communication is an auxiliary road to the main highway. Proper “Stop” and “Yield” signs for glial-derived communication may buffer and modulate deleterious neuronal activity in pain pathways.
Abbadie, C., Lindia, J. A., Cumiskey, A. M., Peterson, L. B., Mudgett, J. S., Bayne, E. K., … Forrest, M. J. (2003). Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2. Proceedings of the National Academy of Sciences of the United States of America, 100(13), 7947–7952. doi:10.1073/pnas.1331358100Find this resource:
Abbas, A. O., Donovan, M. D., & Salem, A. K. (2008). Formulating poly(lactide-co-glycolide) particles for plasmid DNA delivery. Journal of Pharmaceutical Sciences, 97(7), 2448–2461. doi:10.1002/jps.21215Find this resource:
Acheson, A., Conover, J. C., Fandl, J. P., DeChiara, T. M., Russell, M., Thadani, A., … Lindsay, R. M. (1995). A BDNF autocrine loop in adult sensory neurons prevents cell death. Nature, 374(6521), 450–453. doi:10.1038/374450a0Find this resource:
Albrecht, D. S., Ahmed, S. U., Kettner, N. W., Borra, R. J. H., Cohen-Adad, J., Deng, H., … Zhang, Y. (2018). Neuroinflammation of the spinal cord and nerve roots in chronic radicular pain patients. Pain, 159(5), 968–977. doi:10.1097/j.pain.0000000000001171Find this resource:
Allen, N. J., & Eroglu, C. (2017). Cell biology of astrocyte-synapse interactions. Neuron, 96(3), 697–708. doi:10.1016/j.neuron.2017.09.056Find this resource:
Allis, C. D., & Jenuwein, T. (2016). The molecular hallmarks of epigenetic control. Nature Reviews. Genetics, 17(8), 487–500. doi:10.1038/nrg.2016.59Find this resource:
Askew, K., Li, K., Olmos-Alonso, A., Garcia-Moreno, F., Liang, Y., Richardson, P., … Gomez-Nicola, D. (2017). Coupled proliferation and apoptosis maintain the rapid turnover of microglia in the adult brain. Cell Reports, 18(2), 391–405. doi:10.1016/j.celrep.2016.12.041Find this resource:
Backonja, M. M., Coe, C. L., Muller, D. A., & Schell, K. (2008). Altered cytokine levels in the blood and cerebrospinal fluid of chronic pain patients. Journal of Neuroimmunology, 195(1–2), 157–163. doi:10.1016/j.jneuroim.2008.01.005Find this resource:
Bazan, J. F., Bacon, K. B., Hardiman, G., Wang, W., Soo, K., Rossi, D., … Schall, T. J. (1997). A new class of membrane-bound chemokine with a CX3C motif. Nature, 385(6617), 640–644. doi:10.1038/385640a0Find this resource:
Berger, S. L., Kouzarides, T., Shiekhattar, R., & Shilatifard, A. (2009). An operational definition of epigenetics. Genes & Development, 23(7), 781–783. doi:10.1101/gad.1787609Find this resource:
Bianchi, M., Sacerdote, P., Ricciardi-Castagnoli, P., Mantegazza, P., & Panerai, A. E. (1992). Central effects of tumor necrosis factor alpha and interleukin-1 alpha on nociceptive thresholds and spontaneous locomotor activity. Neuroscience Letters, 148(1–2), 76–80.Find this resource:
Bittar, A., Jun, J., La, J.-H., Wang, J., Leem, J. W., & Chung, J. M. (2017). Reactive oxygen species affect spinal cell type-specific synaptic plasticity in a model of neuropathic pain. Pain, 158(11), 2137–2146. doi:10.1097/j.pain.0000000000001014Find this resource:
Block, M. L., Zecca, L., & Hong, J.-S. (2007). Microglia-mediated neurotoxicity: Uncovering the molecular mechanisms. Nature Reviews. Neuroscience, 8(1), 57–69. doi:10.1038/nrn2038Find this resource:
Boka, G., Anglade, P., Wallach, D., Javoy-Agid, F., Agid, Y., & Hirsch, E. C. (1994). Immunocytochemical analysis of tumor necrosis factor and its receptors in Parkinson’s disease. Neuroscience Letters, 172(1–2), 151–154.Find this resource:
Braza, F., Brouard, S., Chadban, S., & Goldstein, D. R. (2016). Role of TLRs and DAMPs in allograft inflammation and transplant outcomes. Nature Reviews. Nephrology, 12(5), 281–290. doi:10.1038/nrneph.2016.41Find this resource:
Burmeister, A. R., Johnson, M. B., Chauhan, V. S., Moerdyk-Schauwecker, M. J., Young, A. D., Cooley, I. D., … Marriott, I. (2017). Human microglia and astrocytes constitutively express the neurokinin-1 receptor and functionally respond to substance P. Journal of Neuroinflammation, 14(1), 245. doi:10.1186/s12974-017-1012-5Find this resource:
Chen, G., Park, C.-K., Xie, R.-G., Berta, T., Nedergaard, M., & Ji, R.-R. (2014). Connexin-43 induces chemokine release from spinal cord astrocytes to maintain late-phase neuropathic pain in mice. Brain: A Journal of Neurology, 137(Pt. 8), 2193–2209. doi:10.1093/brain/awu140Find this resource:
Chen, J. T., Guo, D., Campanelli, D., Frattini, F., Mayer, F., Zhou, L., … Hu, J. (2014). Presynaptic GABAergic inhibition regulated by BDNF contributes to neuropathic pain induction. Nature Communications, 5, 5331. doi:10.1038/ncomms6331Find this resource:
Chen, W., Walwyn, W., Ennes, H. S., Kim, H., McRoberts, J. A., & Marvizón, J. C. G. (2014). BDNF released during neuropathic pain potentiates NMDA receptors in primary afferent terminals. The European Journal of Neuroscience, 39(9), 1439–1454. doi:10.1111/ejn.12516Find this resource:
Choi, S.-R., Moon, J.-Y., Roh, D.-H., Yoon, S.-Y., Kwon, S.-G., Choi, H.-S., … Lee, J.-H. (2017). Spinal D-serine increases PKC-dependent GluN1 phosphorylation contributing to the sigma-1 receptor-induced development of mechanical allodynia in a mouse model of neuropathic pain. The Journal of Pain: Official Journal of the American Pain Society, 18(4), 415–427. doi:10.1016/j.jpain.2016.12.002Find this resource:
Clark, A. K., Yip, P. K., Grist, J., Gentry, C., Staniland, A. A., Marchand, F., … Malcangio, M. (2007). Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proceedings of the National Academy of Sciences of the United States of America, 104(25), 10655–10660. doi:10.1073/pnas.0610811104Find this resource:
Colburn, R. W., Rickman, A. J., & DeLeo, J. A. (1999). The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior. Experimental Neurology, 157(2), 289–304. doi:10.1006/exnr.1999.7065Find this resource:
Coull, J. A. M., Beggs, S., Boudreau, D., Boivin, D., Tsuda, M., Inoue, K., … De Koninck, Y. (2005). BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature, 438(7070), 1017–1021. doi:10.1038/nature04223Find this resource:
Coull, J. A. M., Boudreau, D., Bachand, K., Prescott, S. A., Nault, F., Sík, A., … De Koninck, Y. (2003). Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature, 424(6951), 938–942. doi:10.1038/nature01868Find this resource:
Curtis, A. M., Bellet, M. M., Sassone-Corsi, P., & O’Neill, L. A. J. (2014). Circadian clock proteins and immunity. Immunity, 40(2), 178–186. doi:10.1016/j.immuni.2014.02.002Find this resource:
Danbolt, N. C. (2001). Glutamate uptake. Progress in Neurobiology, 65(1), 1–105.Find this resource:
Dancy, B. M., & Cole, P. A. (2015). Protein lysine acetylation by p300/CBP. Chemical Reviews, 115(6), 2419–2452. doi:10.1021/cr500452kFind this resource:
Das, V., Kc, R., Li, X., Varma, D., Qiu, S., Kroin, J. S., … Im, H.-J. (2018). Pharmacological targeting of the mammalian clock reveals a novel analgesic for osteoarthritis-induced pain. Gene, 655, 1–12. doi:10.1016/j.gene.2018.02.048Find this resource:
DeLeo, J., Toth, L., Schubert, P., Rudolphi, K., & Kreutzberg, G. W. (1987). Ischemia-induced neuronal cell death, calcium accumulation, and glial response in the hippocampus of the Mongolian gerbil and protection by propentofylline (HWA 285). Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism, 7(6), 745–751. doi:10.1038/jcbfm.1987.129Find this resource:
Denk, F., Crow, M., Didangelos, A., Lopes, D. M., & McMahon, S. B. (2016). Persistent alterations in microglial enhancers in a model of chronic pain. Cell Reports, 15(8), 1771–1781. doi:10.1016/j.celrep.2016.04.063Find this resource:
Dhandapani, R., Arokiaraj, C. M., Taberner, F. J., Pacifico, P., Raja, S., Nocchi, L., … Heppenstall, P. A. (2018). Control of mechanical pain hypersensitivity in mice through ligand-targeted photoablation of TrkB-positive sensory neurons. Nature Communications, 9(1), 1640. doi:10.1038/s41467-018-04049-3Find this resource:
Ding, X., Cai, J., Li, S., Liu, X.-D., Wan, Y., & Xing, G.-G. (2015). BDNF contributes to the development of neuropathic pain by induction of spinal long-term potentiation via SHP2 associated GluN2B-containing NMDA receptors activation in rats with spinal nerve ligation. Neurobiology of Disease, 73, 428–451. doi:10.1016/j.nbd.2014.10.025Find this resource:
Dougherty, K. D., Dreyfus, C. F., & Black, I. B. (2000). Brain-derived neurotrophic factor in astrocytes, oligodendrocytes, and microglia/macrophages after spinal cord injury. Neurobiology of Disease, 7(6, Pt. B), 574–585. doi:10.1006/nbdi.2000.0318Find this resource:
Dupont, C., Armant, D. R., & Brenner, C. A. (2009). Epigenetics: Definition, mechanisms and clinical perspective. Seminars in Reproductive Medicine, 27(5), 351–357. doi:10.1055/s-0029-1237423Find this resource:
Eijkelkamp, N., Steen-Louws, C., Hartgring, S. A. Y., Willemen, H. L. D. M., Prado, J., Lafeber, F. P. J. G., … Kavelaars, A. (2016). IL4-10 fusion protein is a novel drug to treat persistent inflammatory pain. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 36(28), 7353–7363. doi:10.1523/JNEUROSCI.0092-16.2016Find this resource:
Falnikar, A., Hala, T. J., Poulsen, D. J., & Lepore, A. C. (2016). GLT1 overexpression reverses established neuropathic pain-related behavior and attenuates chronic dorsal horn neuron activation following cervical spinal cord injury. Glia, 64(3), 396–406. doi:10.1002/glia.22936Find this resource:
Feldman, P., Due, M. R., Ripsch, M. S., Khanna, R., & White, F. A. (2012). The persistent release of HMGB1 contributes to tactile hyperalgesia in a rodent model of neuropathic pain. Journal of Neuroinflammation, 9, 180. doi:10.1186/1742-2094-9-180Find this resource:
Ferreira, S. H., Lorenzetti, B. B., Bristow, A. F., & Poole, S. (1988). Interleukin-1 beta as a potent hyperalgesic agent antagonized by a tripeptide analogue. Nature, 334(6184), 698–700. doi:10.1038/334698a0Find this resource:
Finley, A., Chen, Z., Esposito, E., Cuzzocrea, S., Sabbadini, R., & Salvemini, D. (2013). Sphingosine 1-phosphate mediates hyperalgesia via a neutrophil-dependent mechanism. PloS One, 8(1), e55255. doi:10.1371/journal.pone.0055255Find this resource:
Fonken, L. K., Frank, M. G., Kitt, M. M., Barrientos, R. M., Watkins, L. R., & Maier, S. F. (2015). Microglia inflammatory responses are controlled by an intrinsic circadian clock. Brain, Behavior, and Immunity, 45, 171–179. doi:10.1016/j.bbi.2014.11.009Find this resource:
Garrison, C. J., Dougherty, P. M., Kajander, K. C., & Carlton, S. M. (1991). Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury. Brain Research, 565(1), 1–7.Find this resource:
Gomez Perdiguero, E., Klapproth, K., Schulz, C., Busch, K., Azzoni, E., Crozet, L., … Rodewald, H.-R. (2015). Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature, 518(7540), 547–551. doi:10.1038/nature13989Find this resource:
Grace, P. M., Gaudet, A. D., Staikopoulos, V., Maier, S. F., Hutchinson, M. R., Salvemini, D., & Watkins, L. R. (2016). Nitroxidative signaling mechanisms in pathological pain. Trends in Neurosciences, 39(12), 862–879. doi:10.1016/j.tins.2016.10.003Find this resource:
Grace, P. M., Hutchinson, M. R., Maier, S. F., & Watkins, L. R. (2014). Pathological pain and the neuroimmune interface. Nature Reviews. Immunology, 14(4), 217–231. doi:10.1038/nri3621Find this resource:
Grace, P. M., Loram, L. C., Christianson, J. P., Strand, K. A., Flyer-Adams, J. G., Penzkover, K. R., … Watkins, L. R. (2017). Behavioral assessment of neuropathic pain, fatigue, and anxiety in experimental autoimmune encephalomyelitis (EAE) and attenuation by interleukin-10 gene therapy. Brain, Behavior, and Immunity, 59, 49–54. doi:10.1016/j.bbi.2016.05.012Find this resource:
Grace, P. M., Strand, K. A., Galer, E. L., Rice, K. C., Maier, S. F., & Watkins, L. R. (2018). Protraction of neuropathic pain by morphine is mediated by spinal damage associated molecular patterns (DAMPs) in male rats. Brain, Behavior, and Immunity, 72, 45–50. doi:10.1016/j.bbi.2017.08.018Find this resource:
Grace, P. M., Strand, K. A., Galer, E. L., Urban, D. J., Wang, X., Baratta, M. V., … Watkins, L. R. (2016). Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Proceedings of the National Academy of Sciences of the United States of America, 113(24), E3441–E3450. doi:10.1073/pnas.1602070113Find this resource:
Grace, P. M., Wang, X., Strand, K. A., Baratta, M. V., Zhang, Y., Galer, E. L., … Watkins, L. R. (2018). DREADDed microglia in pain: Implications for spinal inflammatory signaling in male rats. Experimental Neurology, 304, 125–131. doi:10.1016/j.expneurol.2018.03.005Find this resource:
Graeber, M. B., & Kreutzberg, G. W. (1986). Astrocytes increase in glial fibrillary acidic protein during retrograde changes of facial motor neurons. Journal of Neurocytology, 15(3), 363–373.Find this resource:
Guan, Z., Kuhn, J. A., Wang, X., Colquitt, B., Solorzano, C., Vaman, S., … Basbaum, A. I. (2016). Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nature Neuroscience, 19(1), 94–101. doi:10.1038/nn.4189Find this resource:
Guo, C.-H., Bai, L., Wu, H.-H., Yang, J., Cai, G.-H., Wang, X., … Ma, W. (2016). The analgesic effect of rolipram is associated with the inhibition of the activation of the spinal astrocytic JNK/CCL2 pathway in bone cancer pain. International Journal of Molecular Medicine, 38(5), 1433–1442. doi:10.3892/ijmm.2016.2763Find this resource:
Healy, L. M., & Antel, J. P. (2016). Sphingosine-1-phosphate receptors in the central nervous and immune systems. Current Drug Targets, 17(16), 1841–1850.Find this resource:
Hildebrand, M. E., Xu, J., Dedek, A., Li, Y., Sengar, A. S., Beggs, S., … Salter, M. W. (2016). Potentiation of synaptic GluN2B NMDAR currents by Fyn kinase is gated through BDNF-mediated disinhibition in spinal pain processing. Cell Reports, 17(10), 2753–2765. doi:10.1016/j.celrep.2016.11.024Find this resource:
Hsieh, M.-C., Lai, C.-Y., Ho, Y.-C., Wang, H.-H., Cheng, J.-K., Chau, Y.-P., & Peng, H.-Y. (2016). Tet1-dependent epigenetic modification of BDNF expression in dorsal horn neurons mediates neuropathic pain in rats. Scientific Reports, 6, 37411. doi:10.1038/srep37411Find this resource:
Huang, E. J., & Reichardt, L. F. (2001). Neurotrophins: Roles in neuronal development and function. Annual Review of Neuroscience, 24, 677–736. doi:10.1146/annurev.neuro.24.1.677Find this resource:
Hutchinson, M. R., Ramos, K. M., Loram, L. C., Wieseler, J., Sholar, P. W., Kearney, J. J., … Watkins, L. R. (2009). Evidence for a role of heat shock protein-90 in toll like receptor 4 mediated pain enhancement in rats. Neuroscience, 164(4), 1821–1832. doi:10.1016/j.neuroscience.2009.09.046Find this resource:
Imai, S., Ikegami, D., Yamashita, A., Shimizu, T., Narita, M., Niikura, K., … Narita, M. (2013). Epigenetic transcriptional activation of monocyte chemotactic protein 3 contributes to long-lasting neuropathic pain. Brain: A Journal of Neurology, 136(Pt. 3), 828–843. doi:10.1093/brain/aws330Find this resource:
Imai, T., Hieshima, K., Haskell, C., Baba, M., Nagira, M., Nishimura, M., … Yoshie, O. (1997). Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion. Cell, 91(4), 521–530.Find this resource:
Inoue, K., & Tsuda, M. (2018). Microglia in neuropathic pain: Cellular and molecular mechanisms and therapeutic potential. Nature Reviews. Neuroscience, 19(3), 138–152. doi:10.1038/nrn.2018.2Find this resource:
Jancalek, R., Svizenska, I., Klusakova, I., & Dubovy, P. (2011). Bilateral changes of IL-10 protein in lumbar and cervical dorsal root ganglia following proximal and distal chronic constriction injury of peripheral nerve. Neuroscience Letters, 501(2), 86–91. doi:10.1016/j.neulet.2011.06.052Find this resource:
Jensen, C. J., Massie, A., & De Keyser, J. (2013). Immune players in the CNS: The astrocyte. Journal of Neuroimmune Pharmacology: The Official Journal of the Society on NeuroImmune Pharmacology, 8(4), 824–839. doi:10.1007/s11481-013-9480-6Find this resource:
Ji, R.-R., Xu, Z.-Z., & Gao, Y.-J. (2014). Emerging targets in neuroinflammation-driven chronic pain. Nature Reviews. Drug Discovery, 13(7), 533–548. doi:10.1038/nrd4334Find this resource:
Junker, U., & Wirz, S. (2010). Review article: Chronobiology: Influence of circadian rhythms on the therapy of severe pain. Journal of Oncology Pharmacy Practice: Official Publication of the International Society of Oncology Pharmacy Practitioners, 16(2), 81–87. doi:10.1177/1078155209337665Find this resource:
Kami, K., Taguchi, S., Tajima, F., & Senba, E. (2016). Histone acetylation in microglia contributes to exercise-induced hypoalgesia in neuropathic pain model mice. The Journal of Pain: Official Journal of the American Pain Society, 17(5), 588–599. doi:10.1016/j.jpain.2016.01.471Find this resource:
Kaneda, Y. (2001). Gene therapy: A battle against biological barriers. Current Molecular Medicine, 1(4), 493–499.Find this resource:
Kato, J., Agalave, N. M., & Svensson, C. I. (2016). Pattern recognition receptors in chronic pain: Mechanisms and therapeutic implications. European Journal of Pharmacology, 788, 261–273. doi:10.1016/j.ejphar.2016.06.039Find this resource:
Kato, J., & Svensson, C. I. (2015). Role of extracellular damage-associated molecular pattern molecules (DAMPs) as mediators of persistent pain. Progress in Molecular Biology and Translational Science, 131, 251–279. doi:10.1016/bs.pmbts.2014.11.014Find this resource:
Kawasaki, Y., Zhang, L., Cheng, J.-K., & Ji, R.-R. (2008). Cytokine mechanisms of central sensitization: Distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 28(20), 5189–5194. doi:10.1523/JNEUROSCI.3338-07.2008Find this resource:
Keller, A. F., Beggs, S., Salter, M. W., & De Koninck, Y. (2007). Transformation of the output of spinal lamina I neurons after nerve injury and microglia stimulation underlying neuropathic pain. Molecular Pain, 3, 27. doi:10.1186/1744-8069-3-27Find this resource:
Kent, S., Bluthé, R. M., Kelley, K. W., & Dantzer, R. (1992). Sickness behavior as a new target for drug development. Trends in Pharmacological Sciences, 13(1), 24–28.Find this resource:
Kettenmann, H., & Verkhratsky, A. (2008). Neuroglia: The 150 years after. Trends in Neurosciences, 31(12), 653–659. doi:10.1016/j.tins.2008.09.003Find this resource:
Kim, D., You, B., Jo, E.-K., Han, S.-K., Simon, M. I., & Lee, S. J. (2010). NADPH oxidase 2-derived reactive oxygen species in spinal cord microglia contribute to peripheral nerve injury-induced neuropathic pain. Proceedings of the National Academy of Sciences of the United States of America, 107(33), 14851–14856. doi:10.1073/pnas.1009926107Find this resource:
King, A., Balaji, S., Le, L. D., Crombleholme, T. M., & Keswani, S. G. (2014). Regenerative wound healing: The role of interleukin-10. Advances in Wound Care, 3(4), 315–323. doi:10.1089/wound.2013.0461Find this resource:
Kobayashi, K., Yamanaka, H., Fukuoka, T., Dai, Y., Obata, K., & Noguchi, K. (2008). P2Y12 receptor upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 28(11), 2892–2902. doi:10.1523/JNEUROSCI.5589-07.2008Find this resource:
Kwilasz, A. J., Grace, P. M., Serbedzija, P., Maier, S. F., & Watkins, L. R. (2015a). The therapeutic potential of interleukin-10 in neuroimmune diseases. Neuropharmacology, 96(Pt. A), 55–69. doi:10.1016/j.neuropharm.2014.10.020Find this resource:
Kwilasz, A. J., Grace, P. M., Serbedzija, P., Maier, S. F., & Watkins, L. R. (2015b). The therapeutic potential of interleukin-10 in neuroimmune diseases. Neuropharmacology, 96(Pt. A), 55–69. doi:10.1016/j.neuropharm.2014.10.020Find this resource:
Lacagnina, M. J., Watkins, L. R., & Grace, P. M. (2018). Toll-like receptors and their role in persistent pain. Pharmacology & Therapeutics, 184, 145–158. doi:10.1016/j.pharmthera.2017.10.006Find this resource:
Lavisse, S., Inoue, K., Jan, C., Peyronneau, M. A., Petit, F., Goutal, S., … Hantraye, P. (2015). [18F]DPA-714 PET imaging of translocator protein TSPO (18 kDa) in the normal and excitotoxically-lesioned nonhuman primate brain. European Journal of Nuclear Medicine and Molecular Imaging, 42(3), 478–494. doi:10.1007/s00259-014-2962-9Find this resource:
Lee, J.-E., Wang, C., Xu, S., Cho, Y.-W., Wang, L., Feng, X., … Ge, K. (2013). H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. ELife, 2, e01503. doi:10.7554/eLife.01503Find this resource:
Lei, W., Mullen, N., McCarthy, S., Brann, C., Richard, P., Cormier, J., … Streicher, J. M. (2017). Heat-shock protein 90 (Hsp90) promotes opioid-induced anti-nociception by an ERK mitogen-activated protein kinase (MAPK) mechanism in mouse brain. The Journal of Biological Chemistry, 292(25), 10414–10428. doi:10.1074/jbc.M116.769489Find this resource:
Leung, L., & Cahill, C. M. (2010). TNF-alpha and neuropathic pain—A review. Journal of Neuroinflammation, 7, 27. doi:10.1186/1742-2094-7-27Find this resource:
Li, J., Deng, G., Wang, H., Yang, M., Yang, R., Li, X., … Yuan, H. (2017). Interleukin-1β pre-treated bone marrow stromal cells alleviate neuropathic pain through CCL7-mediated inhibition of microglial activation in the spinal cord. Scientific Reports, 7, 42260. doi:10.1038/srep42260Find this resource:
Li, S., Cai, J., Feng, Z.-B., Jin, Z.-R., Liu, B.-H., Zhao, H.-Y., … Xing, G.-G. (2017). BDNF contributes to spinal long-term potentiation and mechanical hypersensitivity via Fyn-mediated phosphorylation of NMDA receptor GluN2B subunit at tyrosine 1472 in rats following spinal nerve ligation. Neurochemical Research, 42(10), 2712–2729. doi:10.1007/s11064-017-2274-0Find this resource:
Liddelow, S. A., & Barres, B. A. (2017). Reactive astrocytes: Production, function, and therapeutic potential. Immunity, 46(6), 957–967. doi:10.1016/j.immuni.2017.06.006Find this resource:
Liu, T., Gao, Y.-J., & Ji, R.-R. (2012). Emerging role of Toll-like receptors in the control of pain and itch. Neuroscience Bulletin, 28(2), 131–144. doi:10.1007/s12264-012-1219-5Find this resource:
Liu, X.-J., Liu, T., Chen, G., Wang, B., Yu, X.-L., Yin, C., & Ji, R.-R. (2016). TLR signaling adaptor protein MyD88 in primary sensory neurons contributes to persistent inflammatory and neuropathic pain and neuroinflammation. Scientific Reports, 6, 28188. doi:10.1038/srep28188Find this resource:
Liu, X.-J., Zhang, Y., Liu, T., Xu, Z.-Z., Park, C.-K., Berta, T., … Ji, R.-R. (2014). Nociceptive neurons regulate innate and adaptive immunity and neuropathic pain through MyD88 adapter. Cell Research, 24(11), 1374–1377. doi:10.1038/cr.2014.106Find this resource:
Local, A., Huang, H., Albuquerque, C. P., Singh, N., Lee, A. Y., Wang, W., … Ren, B. (2018). Identification of H3K4me1-associated proteins at mammalian enhancers. Nature Genetics, 50(1), 73–82. doi:10.1038/s41588-017-0015-6Find this resource:
Loggia, M. L., Chonde, D. B., Akeju, O., Arabasz, G., Catana, C., Edwards, R. R., … Hooker, J. M. (2015). Evidence for brain glial activation in chronic pain patients. Brain: A Journal of Neurology, 138(Pt. 3), 604–615. doi:10.1093/brain/awu377Find this resource:
Lopes, D. M., Malek, N., Edye, M., Jager, S. B., McMurray, S., McMahon, S. B., & Denk, F. (2017). Sex differences in peripheral not central immune responses to pain-inducing injury. Scientific Reports, 7(1), 16460. doi:10.1038/s41598-017-16664-zFind this resource:
Lotze, M. T., & Tracey, K. J. (2005). High-mobility group box 1 protein (HMGB1): Nuclear weapon in the immune arsenal. Nature Reviews. Immunology, 5(4), 331–342. doi:10.1038/nri1594Find this resource:
Lu, Y., Jiang, B.-C., Cao, D.-L., Zhang, Z.-J., Zhang, X., Ji, R.-R., & Gao, Y.-J. (2014). TRAF6 upregulation in spinal astrocytes maintains neuropathic pain by integrating TNF-α and IL-1β signaling. Pain, 155(12), 2618–2629. doi:10.1016/j.pain.2014.09.027Find this resource:
Maier, S. F., Wiertelak, E. P., Martin, D., & Watkins, L. R. (1993). Interleukin-1 mediates the behavioral hyperalgesia produced by lithium chloride and endotoxin. Brain Research, 623(2), 321–324.Find this resource:
Manassero, G., Repetto, I. E., Cobianchi, S., Valsecchi, V., Bonny, C., Rossi, F., & Vercelli, A. (2012). Role of JNK isoforms in the development of neuropathic pain following sciatic nerve transection in the mouse. Molecular Pain, 8, 39. doi:10.1186/1744-8069-8-39Find this resource:
Mansikka, H., Sheth, R. N., DeVries, C., Lee, H., Winchurch, R., & Raja, S. N. (2000). Nerve injury-induced mechanical but not thermal hyperalgesia is attenuated in neurokinin-1 receptor knockout mice. Experimental Neurology, 162(2), 343–349. doi:10.1006/exnr.1999.7336Find this resource:
Mapplebeck, J. C. S., Beggs, S., & Salter, M. W. (2017). Molecules in pain and sex: A developing story. Molecular Brain, 10(1), 9. https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-017-0289-8Find this resource:
Marriott, D., Wilkin, G. P., Coote, P. R., & Wood, J. N. (1991). Eicosanoid synthesis by spinal cord astrocytes is evoked by substance P; possible implications for nociception and pain. Advances in Prostaglandin, Thromboxane, and Leukotriene Research, 21B, 739–741.Find this resource:
Marriott, D. R., Wilkin, G. P., & Wood, J. N. (1991). Substance P-induced release of prostaglandins from astrocytes: Regional specialisation and correlation with phosphoinositol metabolism. Journal of Neurochemistry, 56(1), 259–265.Find this resource:
Mashaghi, A., Marmalidou, A., Tehrani, M., Grace, P. M., Pothoulakis, C., & Dana, R. (2016). Neuropeptide substance P and the immune response. Cellular and Molecular Life Sciences: CMLS, 73(22), 4249–4264. doi:10.1007/s00018-016-2293-zFind this resource:
McKelvey, R., Berta, T., Old, E., Ji, R.-R., & Fitzgerald, M. (2015). Neuropathic pain is constitutively suppressed in early life by anti-inflammatory neuroimmune regulation. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 35(2), 457–466. doi:10.1523/JNEUROSCI.2315-14.2015Find this resource:
Meller, S. T., Dykstra, C., Grzybycki, D., Murphy, S., & Gebhart, G. F. (1994). The possible role of glia in nociceptive processing and hyperalgesia in the spinal cord of the rat. Neuropharmacology, 33(11), 1471–1478.Find this resource:
Milligan, E. D., Langer, S. J., Sloane, E. M., He, L., Wieseler-Frank, J., O’Connor, K., … Watkins, L. R. (2005). Controlling pathological pain by adenovirally driven spinal production of the anti-inflammatory cytokine, interleukin-10. The European Journal of Neuroscience, 21(8), 2136–2148. doi:10.1111/j.1460-9568.2005.04057.xFind this resource:
Milligan, E. D., Sloane, E. M., Langer, S. J., Cruz, P. E., Chacur, M., Spataro, L., … Watkins, L. R. (2005). Controlling neuropathic pain by adeno-associated virus driven production of the anti-inflammatory cytokine, interleukin-10. Molecular Pain, 1, 9. doi:10.1186/1744-8069-1-9Find this resource:
Miraucourt, L. S., Peirs, C., Dallel, R., & Voisin, D. L. (2011). Glycine inhibitory dysfunction turns touch into pain through astrocyte-derived D-serine. Pain, 152(6), 1340–1348. doi:10.1016/j.pain.2011.02.021Find this resource:
Mogil, J. S. (2009). Animal models of pain: Progress and challenges. Nature Reviews. Neuroscience, 10(4), 283–294. doi:10.1038/nrn2606Find this resource:
Moon, J.-Y., Choi, S.-R., Roh, D.-H., Yoon, S.-Y., Kwon, S.-G., Choi, H.-S., … Lee, J.-H. (2015). Spinal sigma-1 receptor activation increases the production of D-serine in astrocytes which contributes to the development of mechanical allodynia in a mouse model of neuropathic pain. Pharmacological Research, 100, 353–364. doi:10.1016/j.phrs.2015.08.019Find this resource:
Morioka, N., Saeki, M., Sugimoto, T., Higuchi, T., Zhang, F. F., Nakamura, Y., … Nakata, Y. (2016). Downregulation of the spinal dorsal horn clock gene Per1 expression leads to mechanical hypersensitivity via c-jun N-terminal kinase and CCL2 production in mice. Molecular and Cellular Neurosciences, 72, 72–83. doi:10.1016/j.mcn.2016.01.007Find this resource:
Mu, A., Weinberg, E., Moulin, D. E., & Clarke, H. (2017). Pharmacologic management of chronic neuropathic pain: Review of the Canadian Pain Society consensus statement. Canadian Family Physician Medecin De Famille Canadien, 63(11), 844–852.Find this resource:
Nahin, R. L. (2015). Estimates of pain prevalence and severity in adults: United States, 2012. The Journal of Pain: Official Journal of the American Pain Society, 16(8), 769–780. doi:10.1016/j.jpain.2015.05.002Find this resource:
Nakamura, Y., Morioka, N., Abe, H., Zhang, F. F., Hisaoka-Nakashima, K., Liu, K., … Nakata, Y. (2013). Neuropathic pain in rats with a partial sciatic nerve ligation is alleviated by intravenous injection of monoclonal antibody to high mobility group box-1. PloS One, 8(8), e73640. doi:10.1371/journal.pone.0073640Find this resource:
Nishimura, H., Akiyama, T., Irei, I., Hamazaki, S., & Sadahira, Y. (2010). Cellular localization of sphingosine-1-phosphate receptor 1 expression in the human central nervous system. The Journal of Histochemistry and Cytochemistry: Official Journal of the Histochemistry Society, 58(9), 847–856. doi:10.1369/jhc.2010.956409Find this resource:
Nishio, N., Taniguchi, W., Sugimura, Y. K., Takiguchi, N., Yamanaka, M., Kiyoyuki, Y., … Nakatsuka, T. (2013). Reactive oxygen species enhance excitatory synaptic transmission in rat spinal dorsal horn neurons by activating TRPA1 and TRPV1 channels. Neuroscience, 247, 201–212. doi:10.1016/j.neuroscience.2013.05.023Find this resource:
Nolan, C. C., & Brown, A. W. (1989). Reversible neuronal damage in hippocampal pyramidal cells with triethyllead: The role of astrocytes. Neuropathology and Applied Neurobiology, 15(5), 441–457.Find this resource:
Paganoni, S., Alshikho, M. J., Zürcher, N. R., Cernasov, P., Babu, S., Loggia, M. L., … Atassi, N. (2018). Imaging of glia activation in people with primary lateral sclerosis. NeuroImage. Clinical, 17, 347–353. doi:10.1016/j.nicl.2017.10.024Find this resource:
Park, C.-K., Lü, N., Xu, Z.-Z., Liu, T., Serhan, C. N., & Ji, R.-R. (2011). Resolving TRPV1- and TNF-α-mediated spinal cord synaptic plasticity and inflammatory pain with neuroprotectin D1. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 31(42), 15072–15085. doi:10.1523/JNEUROSCI.2443-11.2011Find this resource:
Perreau-Lenz, S., Sanchis-Segura, C., Leonardi-Essmann, F., Schneider, M., & Spanagel, R. (2010). Development of morphine-induced tolerance and withdrawal: Involvement of the clock gene mPer2. European Neuropsychopharmacology: The Journal of the European College of Neuropsychopharmacology, 20(7), 509–517. doi:10.1016/j.euroneuro.2010.03.006Find this resource:
Raghavendra, V., Tanga, F., Rutkowski, M. D., & DeLeo, J. A. (2003). Anti-hyperalgesic and morphine-sparing actions of propentofylline following peripheral nerve injury in rats: Mechanistic implications of spinal glia and proinflammatory cytokines. Pain, 104(3), 655–664.Find this resource:
Salvemini, D., Doyle, T., Kress, M., & Nicol, G. (2013). Therapeutic targeting of the ceramide-to-sphingosine 1-phosphate pathway in pain. Trends in Pharmacological Sciences, 34(2), 110–118. doi:10.1016/j.tips.2012.12.001Find this resource:
Sebestyén, M. G., Ludtke, J. J., Bassik, M. C., Zhang, G., Budker, V., Lukhtanov, E. A., … Wolff, J. A. (1998). DNA vector chemistry: The covalent attachment of signal peptides to plasmid DNA. Nature Biotechnology, 16(1), 80–85. doi:10.1038/nbt0198-80Find this resource:
Shaw, J. A., Perry, V. H., & Mellanby, J. (1990). Tetanus toxin-induced seizures cause microglial activation in rat hippocampus. Neuroscience Letters, 120(1), 66–69.Find this resource:
Shibasaki, M., Sasaki, M., Miura, M., Mizukoshi, K., Ueno, H., Hashimoto, S., … Amaya, F. (2010). Induction of high mobility group box-1 in dorsal root ganglion contributes to pain hypersensitivity after peripheral nerve injury. Pain, 149(3), 514–521. doi:10.1016/j.pain.2010.03.023Find this resource:
Sikandar, S., Minett, M. S., Millet, Q., Santana-Varela, S., Lau, J., Wood, J. N., & Zhao, J. (2018). Brain-derived neurotrophic factor derived from sensory neurons plays a critical role in chronic pain. Brain: A Journal of Neurology, 141(4), 1028–1039. doi:10.1093/brain/awy009Find this resource:
Sloane, E., Langer, S., Jekich, B., Mahoney, J., Hughes, T., Frank, M., … Milligan, E. (2009). Immunological priming potentiates non-viral anti-inflammatory gene therapy treatment of neuropathic pain. Gene Therapy, 16(10), 1210–1222. doi:10.1038/gt.2009.79Find this resource:
Soderquist, R. G., Sloane, E. M., Loram, L. C., Harrison, J. A., Dengler, E. C., Johnson, S. M., … Mahoney, M. J. (2010). Release of plasmid DNA-encoding IL-10 from PLGA microparticles facilitates long-term reversal of neuropathic pain following a single intrathecal administration. Pharmaceutical Research, 27(5), 841–854. doi:10.1007/s11095-010-0077-yFind this resource:
Sofroniew, M. V. (2015). Astrocyte barriers to neurotoxic inflammation. Nature Reviews. Neuroscience, 16(5), 249–263. doi:10.1038/nrn3898Find this resource:
Son, S.-J., Lee, K.-M., Jeon, S.-M., Park, E.-S., Park, K.-M., & Cho, H.-J. (2007). Activation of transcription factor c-jun in dorsal root ganglia induces VIP and NPY upregulation and contributes to the pathogenesis of neuropathic pain. Experimental Neurology, 204(1), 467–472. doi:10.1016/j.expneurol.2006.09.020Find this resource:
Sorge, R. E., LaCroix-Fralish, M. L., Tuttle, A. H., Sotocinal, S. G., Austin, J.-S., Ritchie, J., … Mogil, J. S. (2011). Spinal cord Toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 31(43), 15450–15454. doi:10.1523/JNEUROSCI.3859-11.2011Find this resource:
Sorge, R. E., Mapplebeck, J. C. S., Rosen, S., Beggs, S., Taves, S., Alexander, J. K., … Mogil, J. S. (2015). Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nature Neuroscience, 18(8), 1081–1083. doi:10.1038/nn.4053Find this resource:
Sorge, R. E., Trang, T., Dorfman, R., Smith, S. B., Beggs, S., Ritchie, J., … Mogil, J. S. (2012). Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nature Medicine, 18(4), 595–599. doi:10.1038/nm.2710Find this resource:
Stellwagen, D., Beattie, E. C., Seo, J. Y., & Malenka, R. C. (2005). Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 25(12), 3219–3228. doi:10.1523/JNEUROSCI.4486-04.2005Find this resource:
Stellwagen, D., & Malenka, R. C. (2006). Synaptic scaling mediated by glial TNF-alpha. Nature, 440(7087), 1054–1059. doi:10.1038/nature04671Find this resource:
Stockstill, K., Doyle, T. M., Yan, X., Chen, Z., Janes, K., Little, J. W., … Salvemini, D. (2018). Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain. The Journal of Experimental Medicine, 215(5), 1301–1313. doi:10.1084/jem.20170584Find this resource:
Stokes, J. A., Cheung, J., Eddinger, K., Corr, M., & Yaksh, T. L. (2013). Toll-like receptor signaling adapter proteins govern spread of neuropathic pain and recovery following nerve injury in male mice. Journal of Neuroinflammation, 10, 148. doi:10.1186/1742-2094-10-148Find this resource:
Sun, J., & Bhatia, M. (2014). Substance P at the neuro-immune crosstalk in the modulation of inflammation, asthma and antimicrobial host defense. Inflammation & Allergy Drug Targets, 13(2), 112–120.Find this resource:
Sun, W., Zhang, L., & Li, R. (2017). Overexpression of miR-206 ameliorates chronic constriction injury-induced neuropathic pain in rats via the MEK/ERK pathway by targeting brain-derived neurotrophic factor. Neuroscience Letters, 646, 68–74. doi:10.1016/j.neulet.2016.12.047Find this resource:
Taves, S., Berta, T., Liu, D.-L., Gan, S., Chen, G., Kim, Y. H., … Ji, R.-R. (2016). Spinal inhibition of p38 MAP kinase reduces inflammatory and neuropathic pain in male but not female mice: Sex-dependent microglial signaling in the spinal cord. Brain, Behavior, and Immunity, 55, 70–81. doi:10.1016/j.bbi.2015.10.006Find this resource:
Tay, T. L., Hagemeyer, N., & Prinz, M. (2016). The force awakens: Insights into the origin and formation of microglia. Current Opinion in Neurobiology, 39, 30–37. doi:10.1016/j.conb.2016.04.003Find this resource:
Thacker, M. A., Clark, A. K., Bishop, T., Grist, J., Yip, P. K., Moon, L. D. F., … McMahon, S. B. (2009). CCL2 is a key mediator of microglia activation in neuropathic pain states. European Journal of Pain (London, England), 13(3), 263–272. doi:10.1016/j.ejpain.2008.04.017Find this resource:
Tozaki-Saitoh, H., Tsuda, M., Miyata, H., Ueda, K., Kohsaka, S., & Inoue, K. (2008). P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 28(19), 4949–4956. doi:10.1523/JNEUROSCI.0323-08.2008Find this resource:
Tsuda, M., Shigemoto-Mogami, Y., Koizumi, S., Mizokoshi, A., Kohsaka, S., Salter, M. W., & Inoue, K. (2003). P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature, 424(6950), 778–783. doi:10.1038/nature01786Find this resource:
Tumati, S., Largent-Milnes, T. M., Keresztes, A. I., Yamamoto, T., Vanderah, T. W., Roeske, W. R., … Varga, E. V. (2012). Tachykinin NK₁ receptor antagonist co-administration attenuates opioid withdrawal-mediated spinal microglia and astrocyte activation. European Journal of Pharmacology, 684(1–3), 64–70.Find this resource:
Uçeyler, N., Rogausch, J. P., Toyka, K. V., & Sommer, C. (2007). Differential expression of cytokines in painful and painless neuropathies. Neurology, 69(1), 42–49. doi:10.1212/01.wnl.0000265062.92340.a5Find this resource:
Vainchtein, I. D., Chin, G., Cho, F. S., Kelley, K. W., Miller, J. G., Chien, E. C., … Molofsky, A. V. (2018). Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development. Science (New York, NY), 359(6381), 1269–1273. doi:10.1126/science.aal3589Find this resource:
Verge, G. M., Milligan, E. D., Maier, S. F., Watkins, L. R., Naeve, G. S., & Foster, A. C. (2004). Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions. The European Journal of Neuroscience, 20(5), 1150–1160. doi:10.1111/j.1460-9568.2004.03593.xFind this resource:
Viviani, B., Bartesaghi, S., Gardoni, F., Vezzani, A., Behrens, M. M., Bartfai, T., … Marinovich, M. (2003). Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 23(25), 8692–8700.Find this resource:
Wagner, R., & Myers, R. R. (1996). Endoneurial injection of TNF-alpha produces neuropathic pain behaviors. Neuroreport, 7(18), 2897–2901.Find this resource:
Wan, W., Cao, L., Khanabdali, R., Kalionis, B., Tai, X., & Xia, S. (2016). The emerging role of HMGB1 in neuropathic pain: A potential therapeutic target for neuroinflammation. Journal of Immunology Research, 2016, 6430423. doi:10.1155/2016/6430423Find this resource:
Wang, Q., Zhang, S., Liu, T., Wang, H., Liu, K., Wang, Q., & Zeng, W. (2018). Sarm1/Myd88-5 regulates neuronal intrinsic immune response to traumatic axonal injuries. Cell Reports, 23(3), 716–724. doi:10.1016/j.celrep.2018.03.071Find this resource:
Wang, W., Wang, W., Wang, Y., Huang, J., Wu, S., & Li, Y.-Q. (2008). Temporal changes of astrocyte activation and glutamate transporter-1 expression in the spinal cord after spinal nerve ligation-induced neuropathic pain. Anatomical Record (Hoboken, NJ: 2007), 291(5), 513–518. doi:10.1002/ar.20673Find this resource:
Watkins, L. R., Wiertelak, E. P., Goehler, L. E., Smith, K. P., Martin, D., & Maier, S. F. (1994). Characterization of cytokine-induced hyperalgesia. Brain Research, 654(1), 15–26.Find this resource:
Wei, F., Guo, W., Zou, S., Ren, K., & Dubner, R. (2008). Supraspinal glial-neuronal interactions contribute to descending pain facilitation. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 28(42), 10482–10495. doi:10.1523/JNEUROSCI.3593-08.2008Find this resource:
Winkelstein, B. A., Rutkowski, M. D., Sweitzer, S. M., Pahl, J. L., & DeLeo, J. A. (2001). Nerve injury proximal or distal to the DRG induces similar spinal glial activation and selective cytokine expression but differential behavioral responses to pharmacologic treatment. The Journal of Comparative Neurology, 439(2), 127–139.Find this resource:
Wlaschin, J. J., Gluski, J. M., Nguyen, E., Silberberg, H., Thompson, J. H., Chesler, A. T., & Le Pichon, C. E. (2018). Dual leucine zipper kinase is required for mechanical allodynia and microgliosis after nerve injury. ELife, 7, e33910. doi:10.7554/eLife.33910Find this resource:
Wu, S. C., & Zhang, Y. (2010). Active DNA demethylation: Many roads lead to Rome. Nature Reviews. Molecular Cell Biology, 11(9), 607–620. doi:10.1038/nrm2950Find this resource:
Xu, T., Zhang, X.-L., Ou-Yang, H.-D., Li, Z.-Y., Liu, C.-C., Huang, Z.-Z., … Xin, W.-J. (2017). Epigenetic upregulation of CXCL12 expression mediates antitubulin chemotherapeutics-induced neuropathic pain. Pain, 158(4), 637–648. doi:10.1097/j.pain.0000000000000805Find this resource:
Xu, Z.-Z., Zhang, L., Liu, T., Park, J. Y., Berta, T., Yang, R., … Ji, R.-R. (2010). Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions. Nature Medicine, 16(5), 592–597, 1p following 597. doi:10.1038/nm.2123Find this resource:
Yan, X., & Weng, H.-R. (2013). Endogenous interleukin-1β in neuropathic rats enhances glutamate release from the primary afferents in the spinal dorsal horn through coupling with presynaptic N-methyl-d-aspartic acid receptors. The Journal of Biological Chemistry, 288(42), 30544–30557. doi:10.1074/jbc.M113.495465Find this resource:
Yowtak, J., Lee, K. Y., Kim, H. Y., Wang, J., Kim, H. K., Chung, K., & Chung, J. M. (2011). Reactive oxygen species contribute to neuropathic pain by reducing spinal GABA release. Pain, 152(4), 844–852. doi:10.1016/j.pain.2010.12.034Find this resource:
Zhang, J., Li, H., Teng, H., Zhang, T., Luo, Y., Zhao, M., … Sun, Z. S. (2012). Regulation of peripheral clock to oscillation of substance P contributes to circadian inflammatory pain. Anesthesiology, 117(1), 149–160. doi:10.1097/ALN.0b013e31825b4fc1Find this resource:
Zhang, R.-X., Li, A., Liu, B., Wang, L., Ren, K., Zhang, H., … Lao, L. (2008). IL-1ra alleviates inflammatory hyperalgesia through preventing phosphorylation of NMDA receptor NR-1 subunit in rats. Pain, 135(3), 232–239. doi:10.1016/j.pain.2007.05.023Find this resource:
Zhou, J., Wang, F., Xu, C., Zhou, Z., & Zhang, W. (2017). The histone demethylase JMJD2A regulates the expression of BDNF and mediates neuropathic pain in mice. Experimental Cell Research, 361(1), 155–162. doi:10.1016/j.yexcr.2017.10.014Find this resource:
Zhuang, Z.-Y., Kawasaki, Y., Tan, P.-H., Wen, Y.-R., Huang, J., & Ji, R.-R. (2007). Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine. Brain, Behavior, and Immunity, 21(5), 642–651. doi:10.1016/j.bbi.2006.11.003Find this resource: