Fibronectin/integrin system is involved in P2X4 receptor upregulation in the spinal cord and neuropathic pain after nerve injury

Glia ◽  
2008 ◽  
Vol 56 (5) ◽  
pp. 579-585 ◽  
Author(s):  
Makoto Tsuda ◽  
Emika Toyomitsu ◽  
Takayuki Komatsu ◽  
Takahiro Masuda ◽  
Emiko Kunifusa ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Nerve Injury ◽  
P2x4 Receptor ◽  
Receptor Upregulation

Lyn tyrosine kinase is required for P2X4 receptor upregulation and neuropathic pain after peripheral nerve injury

Glia ◽  
2007 ◽  
Vol 56 (1) ◽  
pp. 50-58 ◽  
Author(s):  
Makoto Tsuda ◽  
Hidetoshi Tozaki-Saitoh ◽  
Takahiro Masuda ◽  
Emika Toyomitsu ◽  
Tohru Tezuka ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Peripheral Nerve ◽  
Tyrosine Kinase ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
P2x4 Receptor ◽  
Receptor Upregulation ◽  
Lyn Tyrosine Kinase

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

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.

scholarly journals Role of the immune system in neuropathic pain

2019 ◽  
Vol 20 (1) ◽  
pp. 33-37 ◽  
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.

Sortilins in neuropathic pain

2012 ◽  
Vol 3 (3) ◽  
pp. 183-184
Author(s):  
M. Richner ◽  
O.J. Bjerrum ◽  
Y. De Koninck ◽  
A. Nykjaer ◽  
C.B. Vaegter
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Mechanical Allodynia ◽  
Molecular Mechanisms ◽  
Intrathecal Injection ◽  
Ion Concentration ◽  
Down Regulation

AbstractBackground/aimsThe molecular mechanisms underlying neuropathic pain are incompletely understood, but recent data suggest that down-regulation of the chloride extruding co-transporter KCC2 in spinal cord sensory neurons is critical: Following peripheral nerve injury, activated microglia in the spinal cord release BDNF, which stimulates neuronal TrkB receptors and ultimately results in the reduction of KCC2 levels. Consequently, neuronal intracellular chloride ion concentration increases, impairing GABAA-receptor mediated inhibition. We have previously described how the receptor sortilin modulates neurotrophin signaling by facilitating anterograde transport of Trk receptors. Unpublished data further link SorCS2, another member of the Sortilins family of sorting receptors (sortilin, SorLA and SorCS1–3) to BDNF signaling by regulating presynaptic TrkB trafficking. The purpose of this study is to explore the involvement of Sortilins in neuropathic pain.MethodsWe subjected wild-type (wt), sortilin knockout (Sort1-/-) and SorCS2 knockout (SorCS2-/-) mice to the Spared Nerve Injury (SNI) model of peripheral nerve injury. Mechanical allodynia was measured by von Frey filaments using the up-down-up method and a 3-out-of-5 thresshold.ResultsAs previously described by several groups, wt mice developed significant mechanical allodynia following SNI. Interestingly however, mice lacking sortilin or SorCS2 were fully protected from development of allodynia and did not display KCC2 down-regulation following injury. In addition, a single intrathecal injection of antibodies against sortilin or SorCS2 could delay or rescue mechanical allodynia in wt SNI mice for 2-3 days. Finally, neither sortilin nor SorCS2 deficient mice responded to intrathecal injection of BDNF, in contrast to wt mice which developed transient mechanical allodynia.ConclusionWe hypothesize that sortilin and SorCS2 are involved in neuropathic pain development by regulating TrkB signaling. Alternatively, Sortilins may directly influence the regulation of KCC2 membrane levels following injury. Both hypotheses are currently being investigated by our group.

CB2/miR-124 signaling down-regulate the expression of purinergic P2X4 and P2X7 receptor in dorsal spinal cord of CCI rats

2020 ◽  
Author(s):  
Rui Xu ◽  
Fan Yang ◽  
Lijuan Li ◽  
Xiaohong Liu ◽  
Xiaolu Lei ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Nerve Injury ◽  
Intrathecal Injection ◽  
Receptor Activation ◽  
Cb2 Receptor ◽  
Dorsal Spinal Cord ◽  
P38mapk Pathway ◽  
Dorsal Spinal

Abstract Background: The importance of P2X purinoceptors, CB2 receptor and microRNA-124(miR-124) in spinal cord microglia to the development of neuropathic pain was demonstrated in numerous previous studies. The upregulation of P2X4 and P2X7 receptors in spinal dorsal horn microglia is involved in the development of pain behavior caused by peripheral nerve injury. However, it is not clear whether the expression of P2X4 and P2X7 receptors at dorsal spinal cord will be influenced by CB2 receptor or miR-124 in rats after chronic sciatic nerve injury.Methods: Chronic constriction injury (CCI) of the sciatic nerve was performed in rats to induce neuropathic pain. Tests of the mechanical withdrawal threshold (MWT) were carried out to assess the response of the paw to mechanical stimulus. The expression of miR-124, P2X4, P2X7 and CB2 receptor were detected with RT-PCR. The protein expression of P2X4, P2X7 and CB2 receptor, RhoA, ROCK1, ROCK2, p-p38MAPK and p-NF-kappaBp65 was detected with Western blotting analysis. Results: Intrathecal administration of CB2 receptor agonist AM1241 significantly attenuated CCI-induced mechanical allodynia and significantly inhibited the increased expression of P2X4 and P2X7 receptors at the mRNA and protein levels, which imply that P2X4 and P2X7 receptors expression are down-regulated by AM1241 in CCI rats. Western blot analysis showed that AM1241 suppressed the elevated expression of RhoA, ROCK1, ROCK2, p-p38MAPK and NF-κBp65 in the dorsal spinal cord induced by CCI. After administration with Y-27632 (ROCK inhibitor), SB203580 (P38MAPK inhibitor) or PDTC (NF-κB inhibitor), the levels of P2X4 and P2X7 receptors expression in the dorsal spinal cord were lower than those in CCI rats, which imply that the ROCK/P38MAPK pathway and NF-κB activation may contribute to the increased expression of P2X4 and P2X7 receptor. On the other hand, in CCI rats, AM1241 treatment evoked the increased expression of CB2 receptor and miRNA-124, which can be inhibited by intrathecal injection of CB2 receptor antagonist AM630, which indicate that the increased expression of miRNA-124 may be medicated by CB2 receptor activation. In addition, the increased expression of P2X4 and P2X7 receptors in the dorsal spinal cord of CCI rats were inhibited by miRNA-124 agomir. Furthermore, intrathecal injection of miRNA-124 agomir could efficiently inhibit the ROCK/P38MAPK pathway and NF-κB activation in CCI rats. Moreover, AM1241 treatment significantly inhibited the expression of P2X4 and P2X7 receptors, and this suppression is enhanced by pretreatment with miRNA-124 agomir. On the contrast, the inhibitory effect of AM1241 on the expression of P2X4 and P2X7 receptor can be reversed by pretreatment with miRNA-124 antagomir.Conclusions: In CCI rats, intrathecal injection of AM1241 could efficiently induce the increased expression of miRNA-124, while inhibiting the ROCK/P38MAPK pathway and NF-κB activation in dorsal spinal cord. CB2 receptor/miRNA-124 signaling induced the decreased P2X4 and P2X7 receptors expression via inhibit the ROCK/P38MAPK pathway and NF-κB activation.

scholarly journals Suppression of Superficial Microglial Activation by Spinal Cord Stimulation Attenuates Neuropathic Pain Following Sciatic Nerve Injury in Rats

2020 ◽  
Vol 21 (7) ◽  
pp. 2390
Author(s):  
Masamichi Shinoda ◽  
Satoshi Fujita ◽  
Shiori Sugawara ◽  
Sayaka Asano ◽  
Ryo Koyama ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Electrical Stimulation ◽  
Dorsal Horn ◽  
Nerve Injury ◽  
Spinal Cord Stimulation ◽  
Microglial Activation ◽  
In Vivo Optical Imaging ◽  
Stimulation Of

We evaluated the mechanisms underlying the spinal cord stimulation (SCS)-induced analgesic effect on neuropathic pain following spared nerve injury (SNI). On day 3 after SNI, SCS was performed for 6 h by using electrodes paraspinally placed on the L4-S1 spinal cord. The effects of SCS and intraperitoneal minocycline administration on plantar mechanical sensitivity, microglial activation, and neuronal excitability in the L4 dorsal horn were assessed on day 3 after SNI. The somatosensory cortical responses to electrical stimulation of the hind paw on day 3 following SNI were examined by using in vivo optical imaging with a voltage-sensitive dye. On day 3 after SNI, plantar mechanical hypersensitivity and enhanced microglial activation were suppressed by minocycline or SCS, and L4 dorsal horn nociceptive neuronal hyperexcitability was suppressed by SCS. In vivo optical imaging also revealed that electrical stimulation of the hind paw-activated areas in the somatosensory cortex was decreased by SCS. The present findings suggest that SCS could suppress plantar SNI-induced neuropathic pain via inhibition of microglial activation in the L4 dorsal horn, which is involved in spinal neuronal hyperexcitability. SCS is likely to be a potential alternative and complementary medicine therapy to alleviate neuropathic pain following nerve injury.

scholarly journals Microglial BDNF, PI3K, and p-ERK in the Spinal Cord Are Suppressed by Pulsed Radiofrequency on Dorsal Root Ganglion to Ease SNI-Induced Neuropathic Pain in Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Xueru Xu ◽  
Shaoxiong Fu ◽  
Xiaomei Shi ◽  
Rongguo Liu
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Dorsal Root Ganglion ◽  
Nerve Injury ◽  
Calcium Binding ◽  
Dorsal Root ◽  
Intrathecal Injection ◽  
Pulsed Radiofrequency ◽  
Erk Phosphorylation ◽  
Extracellular Signal

Background. Pulsed radiofrequency (PRF) on the dorsal root ganglion (DRG) has been applied to alleviate neuropathic pain effectively, yet the mechanisms underlying pain reduction owing to this treatment are not clarified completely. The activated microglia, brain-derived neurotrophic factor (BDNF), phosphatidylinositol 3-kinase (PI3K), and phosphorylated extracellular signal-regulated kinase (p-ERK) in the spinal cord were demonstrated to be involved in developing neuropathic pain. Also, it has been just known that PRF on DRG inhibits the microglial activation in nerve injury rats. Here, we aim to investigate whether PRF treatment could regulate the levels of BDNF, PI3K, and p-ERK in the spinal cord of rats with spared nerve injury (SNI) via suppressing the spinal microglia activation to ease neuropathic pain. Methods. The rats with SNI were intrathecally treated with minocycline (specific microglia inhibitor) or same volume of dimethyl sulfoxide once daily, beginning from 1 h before nerve transection to 7 days. PRF was applied adjacent to the L4-L5 DRG of rats with SNI at 45 V for 6 min on the seventh postoperative day, whereas the free-PRF rats were treated without PRF. The withdrawal thresholds were studied, and the spinal levels of ionized calcium-binding adapter molecule 1 (Iba1), BDNF, PI3K, and p-ERK were calculated by western blot analysis, reverse transcription-polymerase chain reaction, and immunofluorescence. Results. The paw withdrawal mechanical threshold and paw withdrawal thermal latency decreased in the ipsilateral hind paws after SNI, and the spinal levels of Iba1, BDNF, PI3K, and p-ERK increased on day 21 after SNI compared with baseline (P<0.01). An intrathecal injection of minocycline led to the reversal of SNI-induced allodynia and increase in levels of Iba1, BDNF, PI3K, and p-ERK. Withdrawal thresholds recovered partially after a single PRF treatment for 14 days, and SNI-induced microglia hyperactivity, BDNF upregulation, and PI3K and ERK phosphorylation in the spinal cord reduced on D14 due to the PRF procedure. Conclusion. Microglial BDNF, PI3K, and p-ERK in the spinal cord are suppressed by the therapy of PRF on DRG to ease SNI-induced neuropathic pain in rats.

scholarly journals Bidirectional Action of Cenicriviroc, a CCR2/CCR5 Antagonist, Results in Alleviation of Pain-Related Behaviors and Potentiation of Opioid Analgesia in Rats With Peripheral Neuropathy

2020 ◽  
Vol 11 ◽  
Author(s):  
Klaudia Kwiatkowski ◽  
Katarzyna Pawlik ◽  
Katarzyna Ciapała ◽  
Anna Piotrowska ◽  
Wioletta Makuch ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Nerve Injury ◽  
Opioid Receptors ◽  
Chemokine Receptors ◽  
Ccr5 Antagonist ◽  
Lumbar Spinal Cord ◽  
Dependent Manner ◽  
Innovative Strategy

Clinical management of neuropathic pain is unsatisfactory, mainly due to its resistance to the effects of available analgesics, including opioids. Converging evidence indicates the functional interactions between chemokine and opioid receptors and their influence on nociceptive processes. Recent studies highlight that the CC chemokine receptors type 2 (CCR2) and 5 (CCR5) seem to be of particular interest. Therefore, in this study, we investigated the effects of the dual CCR2/CCR5 antagonist, cenicriviroc, on pain-related behaviors, neuroimmune processes, and the efficacy of opioids in rats after chronic constriction injury (CCI) of the sciatic nerve. To define the mechanisms of action of cenicriviroc, we studied changes in the activation/influx of glial and immune cells and, simultaneously, the expression level of CCR2, CCR5, and important pronociceptive cytokines in the spinal cord and dorsal root ganglia (DRG). We demonstrated that repeated intrathecal injections of cenicriviroc, in a dose-dependent manner, alleviated hypersensitivity to mechanical and thermal stimuli in rats after sciatic nerve injury, as measured by von Frey and cold plate tests. Behavioral effects were associated with the beneficial impact of cenicriviroc on the activation/influx level of C1q/IBA-1-positive cells in the spinal cord and/or DRG and GFAP-positive cells in DRG. In parallel, administration of cenicriviroc decreased the expression of CCR2 in the spinal cord and CCR5 in DRG. Concomitantly, we observed that the level of important pronociceptive factors (e.g., IL-1beta, IL-6, IL-18, and CCL3) were increased in the lumbar spinal cord and/or DRG 7 days following injury, and cenicriviroc was able to prevent these changes. Additionally, repeated administration of this dual CCR2/CCR5 antagonist enhanced the analgesic effects of morphine and buprenorphine in neuropathic rats, which can be associated with the ability of cenicriviroc to prevent nerve injury-induced downregulation of all opioid receptors at the DRG level. Overall, our results suggest that pharmacological modulation based on the simultaneous blockade of CCR2 and CCR5 may serve as an innovative strategy for the treatment of neuropathic pain, as well as in combination with opioids.

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