Lack of correlation between spinal microgliosis and long-term development of tactile hypersensitivity in two different sciatic nerve crush injury

Microglia activation following peripheral nerve injury has been shown to contribute to central sensitization of the spinal cord for the development of neuropathic pain. In a recent study, we reported that the amount of nerve damage does not necessarily correlate with chronic pain development. Here we compared the response of spinal microglia, using immunohistochemistry as a surrogate of microglial activation, in mice with two different types of crush injury of the sciatic nerve. We confirmed that incomplete crush of the sciatic nerve (partial crush injury, PCI) resulted in tactile hypersensitivity after the recovery of sensory function (15 days after surgery), whereas the hypersensitivity was not observed after the complete crush (full crush injury, FCI). We observed that immunoreactivity for Iba-1, a microglial marker, was greater in the ipsilateral dorsal horn of lumbar (L4) spinal cord of mice 2 days after FCI compared to PCI, positively correlating with the intensity of crush injury. Ipsilateral Iba-1 reactivity was comparable between injuries at 7 days with a significant increase compared to the contralateral side. By day 15 after injury, ipsilateral Iba-1 immunoreactivity was much reduced compared to day 7 and was not different between the groups. Our results suggest that the magnitude of the early microgliosis is dependent on injury severity, but does not necessarily correlate with the long-term development of chronic pain-like hypersensitivity after peripheral nerve injury.

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Reduced Renshaw Recurrent Inhibition after Neonatal Sciatic Nerve Crush in Rats

Neural Plasticity ◽

10.1155/2014/786985 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11

Author(s):

Liang Shu ◽

Jingjing Su ◽

Lingyan Jing ◽

Ying Huang ◽

Yu Di ◽

...

Keyword(s):

Spinal Cord ◽

Sciatic Nerve ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Recurrent Inhibition ◽

Crush Injury ◽

Sciatic Nerve Crush ◽

Nerve Crush ◽

Nerve Crush Injury

Renshaw recurrent inhibition (RI) plays an important gated role in spinal motion circuit. Peripheral nerve injury is a common disease in clinic. Our current research was designed to investigate the change of the recurrent inhibitory function in the spinal cord after the peripheral nerve crush injury in neonatal rat. Sciatic nerve crush was performed on 5-day-old rat puppies and the recurrent inhibition between lateral gastrocnemius-soleus (LG-S) and medial gastrocnemius (MG) motor pools was assessed by conditioning monosynaptic reflexes (MSR) elicited from the sectioned dorsal roots and recorded either from the LG-S and MG nerves by antidromic stimulation of the synergist muscle nerve. Our results demonstrated that the MSR recorded from both LG-S or MG nerves had larger amplitude and longer latency after neonatal sciatic nerve crush. The RI in both LG-S and MG motoneuron pools was significantly reduced to virtual loss (15–20% of the normal RI size) even after a long recovery period upto 30 weeks after nerve crush. Further, the degree of the RI reduction after tibial nerve crush was much less than that after sciatic nerve crush indicatig that the neuron-muscle disconnection time is vital to the recovery of the spinal neuronal circuit function during reinnervation. In addition, sciatic nerve crush injury did not cause any spinal motor neuron loss but severally damaged peripheral muscle structure and function. In conclusion, our results suggest that peripheral nerve injury during neonatal early development period would cause a more sever spinal cord inhibitory circuit damage, particularly to the Renshaw recurrent inhibition pathway, which might be the target of neuroregeneration therapy.

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SUR1, newly expressed in astrocytes, mediates neuropathic pain in a mouse model of peripheral nerve injury

Molecular Pain ◽

10.1177/17448069211006603 ◽

2021 ◽

Vol 17 ◽

pp. 174480692110066

Author(s):

Orest Tsymbalyuk ◽

Volodymyr Gerzanich ◽

Aaida Mumtaz ◽

Sanketh Andhavarapu ◽

Svetlana Ivanova ◽

...

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Sciatic Nerve ◽

Peripheral Nerve ◽

Dorsal Horn ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Thermal Sensitivity ◽

Gradual Improvement ◽

Pain Behaviors

Background Neuropathic pain following peripheral nerve injury (PNI) is linked to neuroinflammation in the spinal cord marked by astrocyte activation and upregulation of interleukin 6 (IL -6 ), chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-X-C motif) ligand 1 (CXCL1), with inhibition of each individually being beneficial in pain models. Methods Wild type (WT) mice and mice with global or pGfap-cre- or pGFAP-cre/ERT2-driven Abcc8/SUR1 deletion or global Trpm4 deletion underwent unilateral sciatic nerve cuffing. WT mice received prophylactic (starting on post-operative day [pod]-0) or therapeutic (starting on pod-21) administration of the SUR1 antagonist, glibenclamide (10 µg IP) daily. We measured mechanical and thermal sensitivity using von Frey filaments and an automated Hargreaves method. Spinal cord tissues were evaluated for SUR1-TRPM4, IL-6, CCL2 and CXCL1. Results Sciatic nerve cuffing in WT mice resulted in pain behaviors (mechanical allodynia, thermal hyperalgesia) and newly upregulated SUR1-TRPM4 in dorsal horn astrocytes. Global and pGfap-cre-driven Abcc8 deletion and global Trpm4 deletion prevented development of pain behaviors. In mice with Abcc8 deletion regulated by pGFAP-cre/ERT2, after pain behaviors were established, delayed silencing of Abcc8 by tamoxifen resulted in gradual improvement over the next 14 days. After PNI, leakage of the blood-spinal barrier allowed entry of glibenclamide into the affected dorsal horn. Daily repeated administration of glibenclamide, both prophylactically and after allodynia was established, prevented or reduced allodynia. The salutary effects of glibenclamide on pain behaviors correlated with reduced expression of IL-6, CCL2 and CXCL1 by dorsal horn astrocytes. Conclusion SUR1-TRPM4 may represent a novel non-addicting target for neuropathic pain.

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Role of the immune system in neuropathic pain

Scandinavian Journal of Pain ◽

10.1515/sjpain-2019-0138 ◽

2019 ◽

Vol 20 (1) ◽

pp. 33-37 ◽

Cited By ~ 16

Author(s):

Marzia Malcangio

Keyword(s):

Spinal Cord ◽

Chronic Pain ◽

Nervous System ◽

Neuropathic Pain ◽

Immune System ◽

Peripheral Nerve ◽

Dorsal Horn ◽

Nerve Injury ◽

Immune Cells ◽

Peripheral Nerve Injury

AbstractBackgroundAcute pain is a warning mechanism that exists to prevent tissue damage, however pain can outlast its protective purpose and persist beyond injury, becoming chronic. Chronic Pain is maladaptive and needs addressing as available medicines are only partially effective and cause severe side effects. There are profound differences between acute and chronic pain. Dramatic changes occur in both peripheral and central pathways resulting in the pain system being sensitised, thereby leading to exaggerated responses to noxious stimuli (hyperalgesia) and responses to non-noxious stimuli (allodynia).Critical role for immune system cells in chronic painPreclinical models of neuropathic pain provide evidence for a critical mechanistic role for immune cells in the chronicity of pain. Importantly, human imaging studies are consistent with preclinical findings, with glial activation evident in the brain of patients experiencing chronic pain. Indeed, immune cells are no longer considered to be passive bystanders in the nervous system; a consensus is emerging that, through their communication with neurons, they can both propagate and maintain disease states, including neuropathic pain. The focus of this review is on the plastic changes that occur under neuropathic pain conditions at the site of nerve injury, the dorsal root ganglia (DRG) and the dorsal horn of the spinal cord. At these sites both endothelial damage and increased neuronal activity result in recruitment of monocytes/macrophages (peripherally) and activation of microglia (centrally), which release mediators that lead to sensitisation of neurons thereby enabling positive feedback that sustains chronic pain.Immune system reactions to peripheral nerve injuriesAt the site of peripheral nerve injury following chemotherapy treatment for cancer for example, the occurrence of endothelial activation results in recruitment of CX3C chemokine receptor 1 (CX3CR1)-expressing monocytes/macrophages, which sensitise nociceptive neurons through the release of reactive oxygen species (ROS) that activate transient receptor potential ankyrin 1 (TRPA1) channels to evoke a pain response. In the DRG, neuro-immune cross talk following peripheral nerve injury is accomplished through the release of extracellular vesicles by neurons, which are engulfed by nearby macrophages. These vesicles deliver several determinants including microRNAs (miRs), with the potential to afford long-term alterations in macrophages that impact pain mechanisms. On one hand the delivery of neuron-derived miR-21 to macrophages for example, polarises these cells towards a pro-inflammatory/pro-nociceptive phenotype; on the other hand, silencing miR-21 expression in sensory neurons prevents both development of neuropathic allodynia and recruitment of macrophages in the DRG.Immune system mechanisms in the central nervous systemIn the dorsal horn of the spinal cord, growing evidence over the last two decades has delineated signalling pathways that mediate neuron-microglia communication such as P2X4/BDNF/GABAA, P2X7/Cathepsin S/Fractalkine/CX3CR1, and CSF-1/CSF-1R/DAP12 pathway-dependent mechanisms.Conclusions and implicationsDefinition of the modalities by which neuron and immune cells communicate at different locations of the pain pathway under neuropathic pain states constitutes innovative biology that takes the pain field in a different direction and provides opportunities for novel approaches for the treatment of chronic pain.

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Neuroprotective potential of erythropoietin and darbepoetin alfa in an experimental model of sciatic nerve injury

Journal of Neurosurgery Spine ◽

10.3171/spi-07/12/645 ◽

2007 ◽

Vol 7 (6) ◽

pp. 645-651 ◽

Cited By ~ 26

Author(s):

Giovanni Grasso ◽

Francesco Meli ◽

Vincenzo Fodale ◽

Gioacchino Calapai ◽

Michele Buemi ◽

...

Keyword(s):

Sciatic Nerve ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Darbepoetin Alfa ◽

Placebo Treatment ◽

Sciatic Nerve Injury ◽

Crush Injury ◽

Sprague Dawley ◽

Compound Muscle Action Potentials

Object The objectives of this study were to examine whether the systemic administration of recombinant human erythropoietin (rHuEPO) and its long-lasting derivative darbepoetin alfa expedited functional recovery in a rat model of sciatic nerve injury, and to compare the effects of these agents in the model. Methods Thirty male Sprague–Dawley rats received a crush injury to the left sciatic nerve and subsequently underwent either placebo treatment, daily injections of rHuEPO, or weekly injections of darbepoetin alfa. Results Both rHuEPO and darbepoetin alfa were effective in reducing neurological impairment and improving compound muscle action potentials following nerve injury. Darbepoetin alfa, however, shortened the duration of peripheral nerve recovery and facilitated recovery from the neurological and electrophysiological impairment following crush injury significantly better than rHuEPO. Examination of the footprint length factor data revealed that darbepoetin alfa–treated animals recovered preinjury function by postoperative Day 10, 4 days earlier than animals treated with rHuEPO and 11 days earlier than animals treated with placebo. Conclusions These results suggest that recovery of neurological function in a model of peripheral nerve injury is more rapid with weekly administration of darbepoetin alfa than with daily rHuEPO treatment. Agents that facilitate nerve regeneration have the potential to limit the extent of motor endplate loss and muscle atrophy. The administration of EPO in its long-lasting recombinant forms affords significant neuroprotection in peripheral nerve injury models and may hold promise for future clinical applications.

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Presence and activation of pro-inflammatory macrophages are associated with CRYAB expression in vitro and after peripheral nerve injury

Journal of Neuroinflammation ◽

10.1186/s12974-021-02108-z ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Erin-Mai F. Lim ◽

Vahid Hoghooghi ◽

Kathleen M. Hagen ◽

Kunal Kapoor ◽

Ariana Frederick ◽

...

Keyword(s):

Sciatic Nerve ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Sciatic Nerve Crush ◽

Nerve Crush ◽

Cytokines And Chemokines ◽

Inflammatory Macrophages ◽

Nerve Crush Injury

Abstract Background Inflammation constitutes both positive and negative aspects to recovery following peripheral nerve injury. Following damage to the peripheral nervous system (PNS), immune cells such as macrophages play a beneficial role in creating a supportive environment for regrowing axons by phagocytosing myelin and axonal debris. However, a prolonged inflammatory response after peripheral nerve injury has been implicated in the pathogenesis of negative symptoms like neuropathic pain. Therefore, the post-injury inflammation must be carefully controlled to prevent secondary damage while allowing for regeneration. CRYAB (also known as alphaB-crystallin/HSPB5) is a small heat shock protein that has many protective functions including an immunomodulatory role in mouse models of multiple sclerosis, spinal cord injury, and stroke. Because its expression wanes and rebounds in the early and late periods respectively after PNS damage, and CRYAB null mice with sciatic nerve crush injury display symptoms of pain, we investigated whether CRYAB is involved in the immune response following PNS injury. Methods Sciatic nerve crush injuries were performed in age-matched Cryab knockout (Cryab−/−) and wildtype (WT) female mice. Nerve segments distal to the injury site were processed by immunohistochemistry for macrophages and myelin while protein lysates of the nerves were analyzed for cytokines and chemokines using Luminex and enzyme-linked immunosorbent assay (ELISA). Peritoneal macrophages from the two genotypes were also cultured and polarized into pro-inflammatory or anti-inflammatory phenotypes where their supernatants were analyzed for cytokines and chemokines by ELISA and protein lysates for macrophage antigen presenting markers using western blotting. Results We report that (1) more pro-inflammatory CD16/32+ macrophages are present in the nerves of Cryab−/− mice at days 14 and 21 after sciatic nerve crush-injury compared to WT counterparts, and (2) CRYAB has an immunosuppressive effect on cytokine secretion [interleukin (IL)-β, IL-6, IL-12p40, tumor necrosis factor (TNF)-α] from pro-inflammatory macrophages in vitro. Conclusions CRYAB may play a role in curbing the potentially detrimental pro-inflammatory macrophage response during the late stages of peripheral nerve regeneration.

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Possible role of antioxidative capacity of (−)-epigallocatechin-3-gallate treatment in morphological and neurobehavioral recovery after sciatic nerve crush injury

Journal of Neurosurgery Spine ◽

10.3171/2016.10.spine16218 ◽

2017 ◽

Vol 27 (5) ◽

pp. 593-613 ◽

Cited By ~ 13

Author(s):

Waleed M. Renno ◽

Ludmil Benov ◽

Khalid M. Khan

Keyword(s):

Spinal Cord ◽

Sciatic Nerve ◽

Nerve Injury ◽

Diameter Ratio ◽

Crush Injury ◽

Sciatic Nerve Crush ◽

Axon Diameter ◽

Nerve Crush ◽

Myelin Thickness ◽

Nerve Crush Injury

OBJECTIVEThis study examined the capacity of the major polyphenolic green tea extract (−)-epigallocatechin-3-gallate (EGCG) to suppress oxidative stress and stimulate the recovery and prompt the regeneration of sciatic nerve after crush injury.METHODSAdult male Wistar rats were randomly assigned to one of 4 groups: 1) Naïve, 2) Sham (sham injury, surgical control group), 3) Crush (sciatic nerve crush injury treated with saline), and 4) Crush+EGCG (sciatic nerve crush injury treated with intraperitoneally administered EGCG, 50 mg/kg). All animals were tested for motor and sensory neurobehavioral parameters throughout the study. Sciatic nerve and spinal cord tissues were harvested and processed for morphometric and stereological analysis. For the biochemical assays, the time points were Day 1, Day 7, Day 14, and Day 28 after nerve injury.RESULTSAfter sciatic nerve crush injury, the EGCG-treated animals (Crush+EGCG group) showed significantly better recovery of foot position and toe spread and 50% greater improvement in motor recovery than the saline-treated animals (Crush group). The Crush+EGCG group displayed an early hopping response at the beginning of the 3rd week postinjury. Animals in the Crush+EGCG group also showed a significant reduction in mechanical allodynia and hyperalgesia latencies and significant improvement in recovery from nociception deficits in both heat withdrawal and tail flick withdrawal latencies compared with the Crush group. In both the Crush+EGCG and Crush groups, quantitative evaluation revealed significant morphological evidence of neuroregeneration according to the following parameters: mean cross-sectional area of axons, myelin thickness in the sciatic nerve (from Week 4 to Week 8), increase of myelin basic protein concentration and gene expression in both the injured sciatic nerve and spinal cord, and fiber diameter to axon diameter ratio and myelin thickness to axon diameter ratio at Week 2 after sciatic nerve injury. However, the axon area remained much smaller in both the Crush+EGCG and Crush groups compared with the Sham and Naïve groups. The number of axons per unit area was significantly decreased in the Crush+EGCG and Crush groups compared with controls. Sciatic nerve injury produced generalized oxidative stress manifested as a significant increase of isoprostanes in the urine and decrease of the total antioxidant capacity (TAC) of the blood from Day 7 until Day 14. EGCG-treated rats showed significantly less increase of isoprostanes than saline-treated animals and also showed full recovery of TAC levels by Day 14 after nerve injury. In spinal cord tissue analysis, EGCG-treated animals showed induced glutathione reductase and suppressed induction of heme oxygenase 1 gene expression compared with nontreated animals.CONCLUSIONSEGCG treatment suppressed the crush-induced production of isoprostanes and stimulated the recovery of the TAC and was associated with remarkable alleviation of motor and sensory impairment and significant histomorphological evidence of neuronal regeneration following sciatic nerve crush injury in rats. The findings of this study suggest that EGCG can be used as an adjunctive therapeutic remedy for nerve injury. However, further investigations are needed to establish the antioxidative mechanism involved in the regenerative process after nerve injury. Only upregulation of glutathione reductase supports the idea that EGCG is acting indirectly via induction of enzymes or transcription factors.

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Bioinformatics analysis of long non-coding RNAs involved in nerve regeneration following sciatic nerve injury

Molecular Pain ◽

10.1177/1744806920971918 ◽

2020 ◽

Vol 16 ◽

pp. 174480692097191

Author(s):

Yuanyuan Jia ◽

Ming Zhang ◽

Pei Li ◽

Wenbo Tang ◽

Yao Liu ◽

...

Keyword(s):

Sciatic Nerve ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Axon Regeneration ◽

Sciatic Nerve Injury ◽

Sciatic Nerve Crush ◽

Non Coding Rnas

Little is known about the role of epigenetic modification in axon regeneration following peripheral nerve injury. The purpose of the present study was to investigate the role of long non-coding RNAs (lncRNAs) in the regulation of axon regeneration. We used bioinformatics to perform microarray analysis and screened total 476 lncRNAs and 129 microRNAs (miRNAs) of differentially expressed genes after sciatic nerve injury in mice. lncRNA-GM4208 and lncRNA-GM30085 were examined, and the changes in lncRNA expression in the L4–L6 dorsal root ganglia (DRG) following sciatic nerve crush injury were analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expression of lncRNAs in the DRG changed, indicating that they might be related to nerve regeneration in the DRG following peripheral nerve injury.

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Magnetic Resonance Imaging as a Biomarker in Rodent Peripheral Nerve Injury Models Reveals an Age-Related Impairment of Nerve Regeneration

Scientific Reports ◽

10.1038/s41598-019-49850-2 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Elisa Giorgetti ◽

Michael Obrecht ◽

Marie Ronco ◽

Moh Panesar ◽

Christian Lambert ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Sciatic Nerve ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Magnetization Transfer Ratio ◽

Sciatic Nerve Crush ◽

Resonance Imaging ◽

Nerve Crush

Abstract Assessment of myelin integrity in peripheral nerve injuries and pathologies has largely been limited to post-mortem analysis owing to the difficulty in obtaining biopsies without affecting nerve function. This is further encumbered by the small size of the tissue and its location. Therefore, the development of robust, non-invasive methods is highly attractive. In this study, we used magnetic resonance imaging (MRI) techniques, including magnetization transfer ratio (MTR), to longitudinally and non-invasively characterize both the sciatic nerve crush and lysolecithin (LCP) demyelination models of peripheral nerve injury in rodents. Electrophysiological, gene expression and histological assessments complemented the extensive MRI analyses in young and aged animals. In the nerve crush model, MTR analysis indicated a slower recovery in regions distal to the site of injury in aged animals, as well as incomplete recovery at six weeks post-crush when analyzing across the entire nerve surface. Similar regional impairments were also found in the LCP demyelination model. This research underlines the power of MTR for the study of peripheral nerve injury in small tissues such as the sciatic nerve of rodents and contributes new knowledge to the effect of aging on recovery after injury. A particular advantage of the approach is the translational potential to human neuropathies.

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Recruitment by SDF-1α of CD34-positive cells involved in sciatic nerve regeneration

Journal of Neurosurgery ◽

10.3171/2011.3.jns101582 ◽

2012 ◽

Vol 116 (2) ◽

pp. 432-444 ◽

Cited By ~ 12

Author(s):

Meei-Ling Sheu ◽

Fu-Chou Cheng ◽

Hong-Lin Su ◽

Ying-Ju Chen ◽

Chun-Jung Chen ◽

...

Keyword(s):

Sciatic Nerve ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Peripheral Nerve Regeneration ◽

Neurological Function ◽

Crush Injury ◽

Local Application ◽

Angiogenesis Factors

Object Increased integration of CD34+ cells in injured nerve significantly promotes nerve regeneration, but this effect can be counteracted by limited migration and short survival of CD34+ cells. SDF-1α and its receptor mediate the recruitment of CD34+ cells involved in the repair mechanism of several neurological diseases. In this study, the authors investigate the potentiation of CD34+ cell recruitment triggered by SDF-1α and the involvement of CD34+ cells in peripheral nerve regeneration. Methods Peripheral nerve injury was induced in 147 Sprague-Dawley rats by crushing the left sciatic nerve with a vessel clamp. The animals were allocated to 3 groups: Group 1, crush injury (controls); Group 2, crush injury and local application of SDF-1α recombinant proteins; and Group 3, crush injury and local application of SDF-1α antibody. Electrophysiological studies and assessment of regeneration markers were conducted at 4 weeks after injury; neurobehavioral studies were conducted at 1, 2, 3, and 4 weeks after injury. The expression of SDF-1α, accumulation of CD34+ cells, immune cells, and angiogenesis factors in injured nerves were evaluated at 1, 3, 7, 10, 14, 21, and 28 days after injury. Results Application of SDF-1α increased the migration of CD34+ cells in vitro, and this effect was dose dependent. Crush injury induced the expression of SDF-1α, with a peak of 10–14 days postinjury, and this increased expression of SDF-1α paralleled the deposition of CD34+ cells, expression of VEGF, and expression of neurofilament. These effects were further enhanced by the administration of SDF-1α recombinant protein and abolished by administration of SDF-1α antibody. Furthermore, these effects were consistent with improvement in measures of neurological function such as sciatic function index, electrophysiological parameters, muscle weight, and myelination of regenerative nerve. Conclusions Expression of SDF-1α facilitates recruitment of CD34+ cells in peripheral nerve injury. The increased deposition of CD34+ cells paralleled significant expression of angiogenesis factors and was consistent with improvement of neurological function. Utilization of SDF-1α for enhancing the recruitment of CD34+ cells involved in peripheral nerve regeneration may be considered as an alternative treatment strategy in peripheral nerve disorders.

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Glia

10.1093/med/9780198834359.003.0035 ◽

2018 ◽

Author(s):

Marzia Malcangio

Keyword(s):

Spinal Cord ◽

Chronic Pain ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Molecular Targets ◽

Translocator Protein ◽

Pivotal Role ◽

Pain Mechanisms ◽

Substantial Body

The landmark review discussed in this chapter, published in 2003 by Watkins and Maier, showed how glia have a major role in the modulation of pain mechanisms in the spinal cord and act remotely from peripheral nerve injury. This review led the way to a substantial body of literature demonstrating the pivotal role played by both microglia and astrocytes in chronic pain mechanisms. Since 2003 the modalities underlying neuron–microglia communication (e.g. chemokines, proteases, the translocator protein TSPO) have been dissected, and novel pathways of interactions delineated. Concrete molecular targets expressed by spinal microglia in response to a remote injury have been identified and they hold promise for future analgesic therapies for chronic pain.

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