Targeting the Microglial Signaling Pathways: New Insights in the Modulation of Neuropathic Pain

Popiołek-Barczyk, Katarzyna; Mika, Joanna

doi:10.2174/0929867323666160607120124

Cited by 148 publications

(106 citation statements)

References 208 publications

(282 reference statements)

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“…There are many reports showing the morphological changes of activated microglia/macrophages after nerve injury in immunofluorescence studies . We observed, using Western blot analysis, a strong increase in the number of IBA‐1‐positive cells on the 7th day post‐CCI in the spinal cord and the DRG, which is in agreement with other data . Many of these works emphasize that the strong uncontrolled activation of microglia/macrophages is the cause of the development of neuropathic pain.…”

Section: Discussionsupporting

confidence: 91%

“…interleukin‐1 β (IL‐1 β ), IL‐18, IL‐6 and nitric oxide synthase 2 (NOS2)] and antinociceptive factors [e.g. IL‐1 receptor antagonist (IL‐1RA), IL‐18 binding protein (IL‐18BP) and IL‐10] contributes to the development of neuropathic pain . Moreover, research on chemokines has suggested that their systems (ligands/receptors) are involved in pathological nociceptive processes .…”

Section: Introductionmentioning

confidence: 99%

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The blockade of CC chemokine receptor type 1 influences the level of nociceptive factors and enhances opioid analgesic potency in a rat model of neuropathic pain

et al. 2020

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Summary A growing body of evidence has indicated that the release of nociceptive factors, such as interleukins and chemokines, by activated immune and glial cells has crucial significance for neuropathic pain generation and maintenance. Moreover, changes in the production of nociceptive immune factors are associated with low opioid efficacy in the treatment of neuropathy. Recently, it has been suggested that CC chemokine receptor type 1 (CCR1) signaling is important for nociception. Our study provides evidence that the development of hypersensitivity in rats following chronic constriction injury (CCI) of the sciatic nerve is associated with significant up‐regulation of endogenous CCR1 ligands, namely, CCL2, CCL3, CCL4, CCL6, CCL7 and CCL9 in the spinal cord and CCL2, CCL6, CCL7 and CCL9 in dorsal root ganglia (DRG). We showed that single and repeated intrathecal administration of J113863 (an antagonist of CCR1) attenuated mechanical and thermal hypersensitivity. Moreover, repeated administration of a CCR1 antagonist enhanced the analgesic properties of morphine and buprenorphine after CCI. Simultaneously, repeated administration of J113863 reduced the protein levels of IBA‐1 in the spinal cord and MPO and CD4 in the DRG and, as a consequence, the level of pronociceptive factors, such as interleukin‐1β (IL‐1β), IL‐6 and IL‐18. The data obtained provide evidence that CCR1 blockade reduces hypersensitivity and increases opioid‐induced analgesia through the modulation of neuroimmune interactions.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

The blockade of CC chemokine receptor type 1 influences the level of nociceptive factors and enhances opioid analgesic potency in a rat model of neuropathic pain

et al. 2020

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“…42 It is well known that ERK 43,44 and PI3K-Akt 27,45 activation are required for the initiation and maintenance of neuropathic pain. Using a PI model, Shi et al.…”

Section: Discussionmentioning

confidence: 99%

CXCL12/CXCR4 signaling-mediated ERK1/2 activation in spinal cord contributes to the pathogenesis of postsurgical pain in rats

et al. 2017

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BackgroundIt has been demonstrated that upregulation of CXCL12 and CXCR4 in spinal cord involves in the pathogenesis of neuropathic, inflammatory, and cancer pain. However, whether CXCL12/CXCR4 signaling contributes to postsurgical pain remains unknown. The aim of the present study is to investigate the role of CXCL12/CXCR4 signaling in the genesis of postsurgical pain and the underlying mechanism.ResultsPlantar incision in rat hind paw resulted in increased expressions of CXCL12 and CXCR4 in spinal dorsal horn. Double immunofluorescence staining revealed that CXCL12 expressed in neurons and astrocytes, and CXCR4 exclusively co-localized with neuronal cells. Prior administration of AMD3100, a specific antagonist of CXCR4, or CXCL12 neutralizing antibody, intrathecally attenuated plantar incision-induced mechanical allodynia and thermal hyperalgesia. Plantar incision also augmented the phosphorylation of NF-κB p65 in spinal cord. Pre intrathecal (i.t.) injection of PDTC, a specific NF-κB activation inhibitor, alleviated plantar incision-induced postsurgical pain and reduced the expression of CXCL12 in spinal cord. Correlated with the upregulation of CXCL12 and CXCR4, plantar incision also resulted in an increased phosphorylation of extracellular signal-regulated kinase 1/2 and Akt in spinal cord. Prior i.t. administration of AMD3100 prevented extracellular signal-regulated kinase, but not Akt, activation in spinal cord. Rats when given a repetitive i.t. PD98059, a specific extracellular signal-regulated kinase inhibitor, started 30 min before surgery also ameliorate plantar incision-induced mechanical and thermal pain hypersensitivity.ConclusionOur results suggests that plantar incision-induced activation of NF-κB signaling may mediate upregulation of CXCL12 in spinal cord, and CXCL12/CXCR4 signaling via extracellular signal-regulated kinase activation contributes to the genesis of postsurgical pain.

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“…NF-κB is a key transcription factor that has been shown to regulate the expression of pro-inflammatory factors involved in activated microglia [30]. A growing body of evidence suggests that inhibition of NF-κB can directly or indirectly promote neuroprotective M2 polarization of the microglia [31,32].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

“…The NF-κB family includes five members (p50, p52, p65, c-Rel, and Rel-B). In the nervous system, the phosphorylation of p65 helps stabilized NF-κB complex in the nucleus for gene expression and thereby is widely used as an indicator of NF-κB activation [30]. In addition, previous studies have reported that p65 phosphorylation induced microglia polarization [35,36].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

The Role of Alpha-Lipoic Acid in the Pathomechanism of Acute Ischemic Stroke

Wang¹,

Lv²,

Sun³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Ischemic stroke results in increased cerebral infarction, neurological deficits and neuroinflammation. The underlying mechanisms involving the anti-inflammatory and neuroprotective properties of α-Lipoic acid (α-LA) remain poorly understood. Herein, we investigated the potential role of α-LA in a middle cerebral artery occlusion (MCAO) rat model and an in vitro lipopolysaccharide (LPS)-induced microglia inflammation model. Methods: In the in vivo study, infarct volume was examined by TTC staining and Garcia score was used to evaluate neurologic recovery. The cytokines were evaluated by enzyme-linked immunosorbent assay, and protein expression of microglia phenotype and NF-κB were measured using western blot. In the in vitro study, the expressions of microglia M1/M2 phenotype were evaluated using qRT-PCR, and immunofluorescence staining was used to assess the nuclear translocation of NF-κB. Results: Both 20 mg/kg and 40 mg/kg of α-LA alleviated infarct size, brain edema, and neurological deficits. Furthermore, α-LA induced the polarization of microglia to the M2 phenotype, modulated the expression of IL-1β, IL-6, TNF-α and IL-10, and attenuated the activation of NF-κB after MCAO. α-LA inhibited the expression of M1 markers, increased activation of the M2 markers, and suppressed the nuclear translocation of NF-κB in LPS-stimulated BV2 microglia. Conclusions: α-LA improved neurological outcome in experimental stroke via modulating microglia M1/M2 polarization. The potential mechanism of α-LA might be mediated by inhibition of NF-κB activation via regulating phosphorylation and nuclear translocation of p65.

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Targeting the Microglial Signaling Pathways: New Insights in the Modulation of Neuropathic Pain

Cited by 148 publications

References 208 publications

The blockade of CC chemokine receptor type 1 influences the level of nociceptive factors and enhances opioid analgesic potency in a rat model of neuropathic pain

The blockade of CC chemokine receptor type 1 influences the level of nociceptive factors and enhances opioid analgesic potency in a rat model of neuropathic pain

CXCL12/CXCR4 signaling-mediated ERK1/2 activation in spinal cord contributes to the pathogenesis of postsurgical pain in rats

The Role of Alpha-Lipoic Acid in the Pathomechanism of Acute Ischemic Stroke

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