Microglia: gatekeepers for neuropathic pain

Microglia: gatekeepers for neuropathic pain

Evolving Concepts

Introduction
Where acute pain protects an individual from further damage, chronic pain serves no adaptive purpose. Approximately 1 in 5 people suffer from chronic pain, which exacts a substantial toll on the both the individual and on national economies [1–3]. Chronic pain can arise due to unresolved inflammation (e.g., rheumatoid arthritis), damage to the nervous system (neuropathic pain), and due to unknown precipitating factors (e.g., fibromyalgia). Specific injuries and diseases that can cause neuropathic pain include traumatic injury (e.g. spinal cord injury), stroke, herpes zoster infection (post-herpetic neuralgia), and multiple sclerosis.

An extensive literature has been devoted to understanding neuropathic pain. Basic science studies have revealed that there are key nervous systems sites for pain modulation. These include the site of injury, the cell bodies of primary afferents (dorsal root ganglia; DRG), the dorsal horn of the spinal cord, and a distributed group of brain regions known as the ‘pain matrix’ [4–7]. Animal studies have predominantly focused on the spinal cord; this site has particular significance for pain, as primary afferent neurons synapse here with pain projection neurons, and are modulated by descending inhibitory neurons and interneurons [5,6]. Therefore, this site will be the focus of this review. Studies in spinal cord have revealed that neuropathic pain is not purely the product of dysfunctional neuronal communication, but that non-neuronal cells, such as microglia, are also critical participants [8,9].

What is the evidence for involvement of microglia in chronic pain?
Microglia are the resident macrophages of the central nervous system (CNS) and play a key role in maintaining homeostasis. Activation of spinal microglia in response to injury of peripheral nerves was first demonstrated in the late 1990s; immunohistochemical and gene expression studies revealed that microglial ‘activation’ markers were rapidly elevated [10,11]. A causal role for microglia in the pain behaviors caused by peripheral nerve injury was then inferred when minocycline treatment was found to prevent pain in rats [12,13]. A key finding of these and subsequent studies (e.g. [14]) was that expression of microglia activation markers peaked within 2 weeks of injury, while inhibition of microglial signaling could prevent, but not reverse, neuropathic pain. This led to the conclusion that microglia participate in the development of neuropathic pain, but not its maintenance. A recent study using Mac1-saporin depletion has claimed that microglia do contribute to the maintenance of neuropathic pain, as their depletion reverses pain behaviors 3 months after nerve injury [15]. However, the consensus view is that microglia are principally early responders to nerve injury.

A limitation to this early research is that pharmacological agents like minocycline also inhibit neurons and astrocytes; the lack of selectivity for microglia confounds interpretation. However, several studies have reinforced evidence for microglial participation in pain. Demonstrating sufficiency for pain, microglia were activated in vitro and then adoptively transferred to naïve male rats, inducing pain behaviors [16]. We have recently expressed Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in spinal microglia, using a cell-selectively promoter [17,18]. Activation of excitatory DREADDs in naïve male rats induced allodynia (sensitivity to innocuous stimuli), supportive of the sufficiency for microglia activation for pain. We also showed that inhibiting microglia with DREADDs could reverse neuropathic pain in males, which demonstrated that microglia are necessary for neuropathic pain.

There is emerging evidence that microglia may contribute to neuropathic pain in a sex-dependent manner. Acute depletion of microglia or inhibition with minocycline reversed neuropathic pain in male rats only [19]. However, these findings are not without controversy [20,21], and additional studies with longer-term treatments are required; when neuropathic pain is fully developed, repeated treatments are often required for reversal. Nonetheless, the accumulating evidence for males-specific engagement of particular signaling pathways will be discussed.

How do microglia become activated after neuronal injury?
Given the evidence that microglia are important cellular mediators of neuropathic pain, investigators next turned to the question of how microglia can respond to nerve injury.
Microglial activation is understood as a change in cell number, morphology, phenotype and motility, the expression of membrane-bound and intracellular signaling proteins, and the release of immunoregulatory products, such as cytokines and chemokines. Microglia express a range of receptors that detect ligands released as a consequence of neuronal injury, and that lead to their activation (illustrated in Fig. 1).

ATP. Injured neurons release ATP in the dorsal horn of the spinal cord [22], which is detected by purinergic receptors expressed by microglia; these include ionotropic P2X4 and P2X7 receptors, and metabotropic P2Y12 and P2Y13 receptors [23,24]. Microglia upregulate surface expression of these receptors after peripheral nerve injury. Their involvement in neuropathic pain has been confirmed in genetic knockout and knockdown studies, as pain behaviors are reduced under these conditions [16,25]. However, the P2X4R pathway is specifically engaged in male rather than female rodents [19,26]. This may be due to differential transcriptional regulation of P2rx4 by the transcription factor IRF5 [26].

Chemokines. Several chemokines are produced and released by injured neurons. At present the strongest evidence supports a role for CSF-1. The cognate receptor CSF-1R is expressed exclusively by microglia in the CNS, and is essential for survival [27]. Peripheral nerve injury induces de novo expression of CSF-1 in the DRG [28]. Conditional knockout of CSF-1 in sensory neurons prevented development of pain behaviors, and reduced microglial activation and proliferation in the spinal dorsal horn [28]. There is evidence that engagement of this pathway may precede activation of microglia via ATP, as the CSF-1R adapter protein DAP12, is upstream of the P2X4R gene.

Other groups have previously suggested that the chemokines CCL2 and CX3CL1 are neuron-glia signals in neuropathic pain [29,30]. However, subsequent studies revealed that microglia express very low levels of CCR2 [31], suggesting a limited role for its ligand CCL2. While microglia uniquely express the receptor for CX3CL1 in the CNS [31], the release of this ligand from neurons is now known to be secondary to microglial activation; CX3CL1 is cleaved by cathepsin S derived from already activated microglia [32]. Furthermore, DAP12 is also upstream of CX3CR1 and cathepsin S genes [28]. Thus, CSF-1 appears to be the principal chemokine to mediate microglial activation after peripheral nerve injury.

Damage associated molecular patterns (DAMPs). According to the danger model of immunogenicity [33], the immune system can respond to cellular damage and the consequent release of DAMPs. Several DAMPs have been implicated in neuropathic pain, including High Mobility Group Box 1 (HMGB1), Heat shock proteins (HSP)-60 and -90, biglycan and fibrinogen [34]. These molecules are typically sequestered within intracellular compartments or the extracellular matrix, and become liberated into the extracellular milieu during stress or damage. It should be noted that the cellular source of many of these DAMPs has not been unequivocally demonstrated. Nonetheless, microglia respond to exogenous administration of DAMPs. Pattern recognition receptors are those capable of detecting such DAMPs, and among this receptor class, Toll-like receptors (TLRs) have been most thoroughly investigated [34].

Of the 13 TLRs expressed in rodents, most research has focused on TLR4. TLR4 is upregulated after peripheral nerve injury. However, evidence for causal involvement in neuropathic pain comes from pharmacological and genetic manipulations: pain behaviors after nerve injury are attenuated when TLR4 or accessory proteins (required for signaling) are inhibited, knocked out, or knocked down [34–36]. There is an emerging role for other TLRs in neuropathic pain, including TLR2, 3, 5, and 9 [34].

Finally, TLR4-dependent pain may be sexually dimorphic. Intrathecal injection of the TLR4 agonist LPS induces allodynia in male (but not female) rats [37]. This is in notable contrast to intrathecal disulfide HMGB1, which induces allodynia in both male and female mice [38]. Reversal of intrathecal LPS-evoked tactile allodynia by the small molecule TLR4 antagonist TAK-242 occurs in male mice, while having no effect on females [39] Similarly, male mice deficient in TLR4 do not develop robust neuropathic pain after peripheral nerve injury, whereas female mice do [40]. This leads to the intriguing possibility of sex differences regarding the involvement of innate immune signaling in the development of neuropathic tactile hypersensitivity. Given the predominance of chronic pain conditions disproportionately afflicting women, it has been argued that interactions between endocrine and immune mechanisms may help explain some of the sex differences observed in the epidemiology of pain disorders [41,42].

Intracellular signaling pathways.Many of the receptors described above converge on common intracellular signaling pathways, including activation of the transcription factor NFB, and p38 and ERK mitogen activated protein kinases (MAPKs). Such activation occurs in spinal microglia after peripheral nerve injury, and leads increased transcription of proinflammatory and pronociceptive cytokines and growth factors [14,43,44]. Other signaling pathways include activation of NADPH oxidase isoform 2 that generate reactive oxygen species [45]. These enzymes and transcription factors are causal to neuropathic pain, as their inhibition or genetic deletion reverses pain behaviors evoked by peripheral nerve injury in male rodents. However, one group has assessed female rodents, and shown that pain behaviors are not reversed when p38 is inhibited [19,46]. This again points to a male-specific role for microglia in neuropathic pain.

How do activated microglia cause pain?
As noted above, a primary consequence of microglial activation is the release of proinflammatory cytokines, growth factors, and reactive oxygen species. These mediators act at central synapses in the spinal cord dorsal horn to disrupt the balance of excitatory and inhibitory neurotransmission (illustrated in Figure 1).

microglia gatekeeprs pain Fig.1

Figure 1. Microglia promote pain sensitization in the dorsal horn of the spinal cord. Injured primary afferent neurons release ATP, chemokines such as CSF-1 and CX3CL1, and danger associated molecular patterns (DAMPs) that activate microglia via surface receptors. Activated microglia release cytokines (IL-1 β, TNF), growth factors (BDNF), and reactive oxygen species (ROS). These signaling mediators act on primary afferent neurons, interneurons, and pain projection neurons to cause neuroexcitation and disinhibition that drives pain sensitization.

Enhanced excitatory synaptic transmission. Cytokines such as TNF and IL-1 increase the excitatory tone of pain projection neurons by enhancing glutamate release and availability [8]. For example, activation of IL-1 receptors that are functionally coupled to presynaptic NMDA receptors promotes glutamate exocytosis [47]. Both IL-1 and TNF can downregulate transporters expressed by astrocytes that are responsible for uptake of glutamate [48,49]; the consequence is excessive glutamate levels in the synaptic cleft. Cytokines and chemokines can also sensitize post-synaptic terminals. The mechanisms include increased trafficking and surface expression of AMPA receptors, and by phosphorylating NMDA receptor subunits [50–53]. Collectively, these studies show that inflammatory mediators released by microglia have the capacity to facilitate hyperexcitability of pain projection neurons.

Reduced inhibitory synaptic transmission. Mediators derived from microglia can also cause disinhibition. Cytokines, chemokines and reactive oxygen species can diminish release of GABA and glycine from interneurons and descending inhibitory projections in the spinal cord [54–56]. Activated microglia also sculpt synaptic elements in the spinal dorsal horn and excessively prune GABAergic terminals [57]. The growth factor BDNF activates TrkB receptors on postsynaptic terminals, reducing expression of the KCC2 potassium-chloride cotransporter [58]. This leads to increased intracellular Cl- concentrations that weaken GABA receptor mediated hyperpolarization. Only males exhibit BDNF-dependent neuropathic pain [19]; this result is consistent with BDNF release requiring P2X4 receptor and p38 MAPK activation, which themselves are activated in a sexually dimorphic manner [26,46]. The consequence of these disinhibitory mechanisms is to increase the excitability of pain projection neurons.

Future directions and conclusions
A major challenge for the future is to translate the findings from animal models into humans. Imaging studies are yielding very promising results using radioligand binding to TSPO, a putative marker of glial activation. Binding was increased in thalamic nuclei, somatosensory cortices of patients with low back pain [59], and the neuroforamina and spinal cords of patients with lumbar radiculopathy [60]. Further work is required to understand the function of TSPO in neuropathic pain and to develop new radioligands. Firstly, it is unclear whether TSPO expression correlates with activation [61]. Secondly, there is some evidence that TSPO has anti-inflammatory function [62], and thus only a subset of glia may be labelled. Which subset that may be, and its relationship to neuropathic pain, need to be defined. Finally, the selectivity of TSPO to microglia is a matter of debate that needs clarification [63]. Nonetheless, these studies provide compelling evidence for the association of glial activation in human chronic pain states. PET imaging may also be a useful tool to validate target engagement for development of novel therapeutics that target microglia.

The vast majority of studies have focused on microglia in the spinal cord. However, the sensory and affective components of chronic pain are ultimately encoded in the brain, as noted above. Several groups, including my own, are now beginning to investigate how microglia in the brain contribute to the multi-dimensional experience of chronic pain [64,65].

The evidence summarized here highlights a critical role for microglia in the initiation of neuropathic pain, especially in male rodents. Given that women predominantly suffer with chronic pain, studies should now be directed towards identifying whether microglia are truly a relevant clinical target for treatment of chronic pain; dysfunctional synaptic plasticity induced by activated microglia is a promising therapeutic avenue for a disease that is poorly managed and causes untold suffering.

Author Affiliations:

Peter M. Grace, PhD – Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030; e: pgrace@mdanderson.org

List of Non-Standard Abbreviations

CNS, central nervous system; DRG, dorsal root ganglia; DREADDs, designer receptor exclusively activated by a designer drug; DAMP, damage associated molecular pattern; IL-1, interleukin-1; TLR, toll-like receptor; TNF, tumor necrosis factor.

References
1. Gaskin DJ, Richard P. The economic costs of pain in the United States. J Pain 2012; 13: 715–24.
2. Nahin RL. Estimates of pain prevalence and severity in adults: United States, 2012. J Pain 2015; 16: 769–80.
3. Pizzo PA, Clark NM. Alleviating suffering 101–pain relief in the United States. N Engl J Med 2012; 366: 197–9.
4. Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and Molecular Mechanisms of Pain. Cell 2009; 139: 267–84.
5. Ossipov MH, Dussor GO, Porreca F. Central modulation of pain. J Clin Invest 2010; 120: 3779–87.
6. Peirs C, Seal RP. Neural circuits for pain: Recent advances and current views. Science 2016; 354: 578–84.
7. Wiech K. Deconstructing the sensation of pain: The influence of cognitive processes on pain perception. Science 2016; 354: 584–7.
8. Grace PM, Hutchinson MR, Maier SF, Watkins LR. Pathological pain and the neuroimmune interface. Nat Rev Immunol 2014; 14: 217–31.
9. Ji R-R, Chamessian A, Zhang Y-Q. Pain regulation by non-neuronal cells and inflammation. Science 2016; 354: 572–7.
10. Colburn RW, DeLeo JA, Rickman AJ, Yeager MP, Kwon P, Hickey WF. Dissociation of microglial activation and neuropathic pain behaviors following peripheral nerve injury in the rat. J Neuroimmunol 1997; 79: 163–75.
11. Tanga FY, Raghavendra V, DeLeo JA. Quantitative real-time RT-PCR assessment of spinal microglial and astrocytic activation markers in a rat model of neuropathic pain. Neurochem Int 2004; 45: 397–407.
12. Ledeboer A, Sloane EM, Milligan ED, et al. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 2005; 115: 71–83.
13. Raghavendra V, Tanga F, DeLeo JA. Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J Pharmacol Exp Ther 2003; 306: 624–30.
14. Jin S-X, Zhuang Z-Y, Woolf CJ, Ji R-R. p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J Neurosci Off J Soc Neurosci 2003; 23: 4017–22.
15. Echeverry S, Shi XQ, Yang M, et al. Spinal microglia are required for long-term maintenance of neuropathic pain. Pain 2017; 158: 1792–801.
16. Tsuda M, Shigemoto-Mogami Y, Koizumi S, et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 2003; 424: 778–83.
17. Grace PM, Strand KA, Galer EL, et al. Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Proc Natl Acad Sci U S A 2016; 113: E3441-3450.
18. Grace PM, Wang X, Strand KA, et al. DREADDed microglia in pain: Implications for spinal inflammatory signaling in male rats. Exp Neurol 2018; 304: 125–31.
19. Sorge RE, Mapplebeck JCS, Rosen S, et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat Neurosci 2015; 18: 1081–3.
20. Costigan M, Moss A, Latremoliere A, et al. T-cell infiltration and signaling in the adult dorsal spinal cord is a major contributor to neuropathic pain-like hypersensitivity. J Neurosci 2009; 29: 14415–22.
21. Krukowski K, Eijkelkamp N, Laumet G, et al. CD8+ T Cells and Endogenous IL-10 Are Required for Resolution of Chemotherapy-Induced Neuropathic Pain. J Neurosci 2016; 36: 11074–83.
22. Masuda T, Ozono Y, Mikuriya S, et al. Dorsal horn neurons release extracellular ATP in a VNUT-dependent manner that underlies neuropathic pain. Nat Commun 2016; 7: 12529.
23. Trang T, Beggs S, Salter MW. ATP receptors gate microglia signaling in neuropathic pain. Exp Neurol 2012; 234: 354–61.
24. Tsuda M. P2 receptors, microglial cytokines and chemokines, and neuropathic pain. J Neurosci Res 2017; 95: 1319–29.
25. Sorge RE, Trang T, Dorfman R, et al. Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nat Med 2012; 18: 595–9.
26. Mapplebeck JCS, Dalgarno R, Tu Y, et al. Microglial P2X4R-evoked pain hypersensitivity is sexually dimorphic in rats. Pain 2018.
27. Elmore MRP, Najafi AR, Koike MA, et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 2014; 82: 380–97.
28. Guan Z, Kuhn JA, Wang X, et al. Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nat Neurosci 2016; 19: 94–101.
29. Abbadie C, Lindia JA, Cumiskey AM, et al. Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2. Proc Natl Acad Sci U S A 2003; 100: 7947–52.
30. Milligan ED, Zapata V, Chacur M, et al. Evidence that exogenous and endogenous fractalkine can induce spinal nociceptive facilitation in rats. Eur J Neurosci 2004; 20: 2294–302.
31. Mizutani M, Pino PA, Saederup N, Charo IF, Ransohoff RM, Cardona AE. The fractalkine receptor but not CCR2 is present on microglia from embryonic development throughout adulthood. J Immunol Baltim Md 1950 2012; 188: 29–36.
32. Clark AK, Yip PK, Malcangio M. The liberation of fractalkine in the dorsal horn requires microglial cathepsin S. J Neurosci Off J Soc Neurosci 2009; 29: 6945–54.
33. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol 1994; 12: 991–1045.
34. Lacagnina MJ, Watkins LR, Grace PM. Toll-like receptors and their role in persistent pain. Pharmacol Ther 2018; 184: 145–58.
35. Hutchinson MR, Zhang Y, Brown K, et al. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4). Eur J Neurosci 2008; 28: 20–9.
36. Tanga FY, Nutile-McMenemy N, DeLeo JA. The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy. Proc Natl Acad Sci U S A 2005; 102: 5856–61.
37. Sorge RE, LaCroix-Fralish ML, Tuttle AH, et al. Spinal cord Toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice. J Neurosci Off J Soc Neurosci 2011; 31: 15450–4.
38. Agalave NM, Larsson M, Abdelmoaty S, et al. Spinal HMGB1 induces TLR4-mediated long-lasting hypersensitivity and glial activation and regulates pain-like behavior in experimental arthritis. Pain 2014; 155: 1802–13.
39. Woller SA, Ravula SB, Tucci FC, et al. Systemic TAK-242 prevents intrathecal LPS evoked hyperalgesia in male, but not female mice and prevents delayed allodynia following intraplantar formalin in both male and female mice: The role of TLR4 in the evolution of a persistent pain state. Brain Behav Immun 2016; 56: 271–80.
40. Stokes JA, Cheung J, Eddinger K, Corr M, Yaksh TL. Toll-like receptor signaling adapter proteins govern spread of neuropathic pain and recovery following nerve injury in male mice. J Neuroinflammation 2013; 10: 148.
41. Mogil JS, Bailey AL. Sex and gender differences in pain and analgesia. Prog Brain Res 2010; 186: 141–57.
42. Nicotra L, Tuke J, Grace PM, Rolan PE, Hutchinson MR. Sex differences in mechanical allodynia: how can it be preclinically quantified and analyzed? Front Behav Neurosci 2014; 8: 40.
43. Ledeboer A, Gamanos M, Lai W, et al. Involvement of spinal cord nuclear factor kappaB activation in rat models of proinflammatory cytokine-mediated pain facilitation. Eur J Neurosci 2005; 22: 1977–86.
44. Zhuang Z-Y, Gerner P, Woolf CJ, Ji R-R. ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain 2005; 114: 149–59.
45. Kim D, You B, Jo E-K, Han S-K, Simon MI, Lee SJ. NADPH oxidase 2-derived reactive oxygen species in spinal cord microglia contribute to peripheral nerve injury-induced neuropathic pain. Proc Natl Acad Sci U S A 2010; 107: 14851–6.
46. Taves S, Berta T, Liu D-L, et al. 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 Behav Immun 2016; 55: 70–81.
47. Yan X, Weng H-R. 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. J Biol Chem 2013; 288: 30544–57.
48. Xin W-J, Weng H-R, Dougherty PM. Plasticity in expression of the glutamate transporters GLT-1 and GLAST in spinal dorsal horn glial cells following partial sciatic nerve ligation. Mol Pain 2009; 5: 15.
49. Yan X, Yadav R, Gao M, Weng H-R. Interleukin-1 beta enhances endocytosis of glial glutamate transporters in the spinal dorsal horn through activating protein kinase C. Glia 2014; 62: 1093–109.
50. Gao X, Kim HK, Chung JM, Chung K. Reactive oxygen species (ROS) are involved in enhancement of NMDA-receptor phosphorylation in animal models of pain. Pain 2007; 131: 262–71.
51. Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature 2006; 440: 1054–9.
52. Stellwagen D, Beattie EC, Seo JY, Malenka RC. Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J Neurosci Off J Soc Neurosci 2005; 25: 3219–28.
53. Zhang R-X, Li A, Liu B, et al. IL-1ra alleviates inflammatory hyperalgesia through preventing phosphorylation of NMDA receptor NR-1 subunit in rats. Pain 2008; 135: 232–9.
54. Gosselin RD, Varela C, Banisadr G, et al. Constitutive expression of CCR2 chemokine receptor and inhibition by MCP-1/CCL2 of GABA-induced currents in spinal cord neurones. J Neurochem 2005; 95: 1023–34.
55. Kawasaki Y, Zhang L, Cheng J-K, Ji R-R. 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. J Neurosci 2008; 28: 5189–94.
56. Yowtak J, Lee KY, Kim HY, et al. Reactive oxygen species contribute to neuropathic pain by reducing spinal GABA release. Pain 2011; 152: 844–52.
57. Batti L, Sundukova M, Murana E, et al. TMEM16F Regulates Spinal Microglial Function in Neuropathic Pain States. Cell Rep 2016; 15: 2608–15.
58. Coull JAM, Beggs S, Boudreau D, et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 2005; 438: 1017–21.
59. Loggia ML, Chonde DB, Akeju O, et al. Evidence for brain glial activation in chronic pain patients. Brain J Neurol 2015; 138: 604–15.
60. Albrecht DS, Ahmed SU, Kettner NW, et al. Neuroinflammation of the spinal cord and nerve roots in chronic radicular pain patients. Pain 2018; 159: 968–77.
61. Owen DR, Narayan N, Wells L, et al. Pro-inflammatory activation of primary microglia and macrophages increases 18 kDa translocator protein expression in rodents but not humans. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 2017; 37: 2679–90.
62. Lee J-W, Nam H, Yu S-W. Systematic Analysis of Translocator Protein 18 kDa (TSPO) Ligands on Toll-like Receptors-mediated Pro-inflammatory Responses in Microglia and Astrocytes. Exp Neurobiol 2016; 25: 262–8.
63. Crawshaw AA, Robertson NP. The role of TSPO PET in assessing neuroinflammation. J Neurol 2017; 264: 1825–7.
64. Grace P, Lacagnina M. Mapping microglial reactivity in the ‘pain matrix’ after peripheral nerve injury. J Pain 2018; 19: S98.
65. Taylor AMW, Castonguay A, Taylor AJ, et al. Microglia disrupt mesolimbic reward circuitry in chronic pain. J Neurosci 2015; 35: 8442–50.

 

Share This Article

Subscribe for Email Notifications

New info on BrainImmune delivered directly to you

You must be logged in to post a comment Login