Microglia in Pain: Detrimental and Protective Roles in Pathogenesis and Resolution of Pain

Chen, Gang; Zhang, Yu‐Qiu; Qadri, Yawar J.; Serhan, Charles N.; Ji, Ru-Rong

doi:10.1016/j.neuron.2018.11.009

Cited by 578 publications

(521 citation statements)

References 246 publications

(334 reference statements)

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“…It is well known that glial cells are involved in pain development . 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 .…”

Section: Discussionsupporting

confidence: 92%

“…66,67 There are many reports showing the morphological changes of activated microglia/macrophages after nerve injury in immunofluorescence studies. 68,69 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. 7,13,15,[70][71][72][73] 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: 92%

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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: 92%

Section: Discussionsupporting

confidence: 92%

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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“…It is well accepted that an exaggerated peripheral nerve input from the site of the injury reaches the spinal cord, leading to many molecular and biochemical changes. Among these changes, previous works have shown that peripheral nerve injury drives an intense proliferation/activation of microglial cells in the dorsal horn of the spinal cord . These events have being correlated to the development of neuropathic pain …”

Section: Introductionmentioning

confidence: 99%

Frontline Science: Blood-circulating leukocytes fail to infiltrate the spinal cord parenchyma after spared nerve injury

Guimarães

Davoli‐Ferreira

Fonseca

et al. 2019

Journal of Leukocyte Biology

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The development of neuropathic pain after peripheral nerve injury involves neuroimmune–glial interactions in the spinal cord. However, whether the development of neuropathic pain depends on the infiltration of peripheral immune cells, such as monocytes, into the spinal cord parenchyma after peripheral nerve damage remains unclear. Here, we used a combination of different techniques such as transgenic reporter mouse (Cx3cr1GFP/+ and Ccr2RFP/+ mice), bone marrow chimeric mice, and parabiosis to investigate this issue in spared nerve injury (SNI) model. Herein, we provided robust evidence that, although microglial cells are activated/proliferate at the dorsal horn of the spinal cord after SNI, peripheral hematopoietic cells (including monocytes) are not able to infiltrate into the spinal cord parenchyma. Furthermore, there was no evidence of CCR2 expression in intrinsic cells of the spinal cord. However, microglial cells activation/proliferation in the spinal cord and mechanical allodynia after SNI were reduced in Ccr2‐deficient mice. These results suggest that blood‐circulating leukocytes cells are not able to infiltrate the spinal cord parenchyma after distal peripheral nerve injury. Nevertheless, they indicate that CCR2‐expressing cells might be indirectly regulating microglia activation/proliferation in the spinal cord after SNI. In conclusion, our study supports that CCR2 inhibition could be explored as an interventional approach to reduce microglia activation and consequently neuropathic pain development after peripheral nerve injury.

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“…Hence, we attempted to clarify whether a lack of Arg2 could regulate neuropathic pain and change pain behaviors. It is also important to note that microglia, the macrophage-like cells in the central nervous system (CNS), have been demonstrated in numerous studies to play a major role in either induction or resolution of pain according to their M1 and M2 microglial phenotypes [16,17]. The M1 and M2 microglial phenotypes contribute to the neuroinflammatory condition by releasing proand anti-inflammatory cytokines respectively, and result in pain behaviors.…”

Section: Introductionmentioning

confidence: 99%

Arginase 2 Deficiency Promotes Neuroinflammation and Pain Behaviors Following Nerve Injury in Mice

Yin

Phạm

Shin

et al. 2020

JCM

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Microglia, the resident macrophages, act as the first and main form of active immune defense in the central nervous system. Arginase 2 (Arg2) is an enzyme involved in L-arginine metabolism and is expressed in macrophages and nervous tissue. In this study, we determined whether the absence of Arg2 plays a beneficial or detrimental role in the neuroinflammatory process. We then investigated whether the loss of Arg2 potentiated microglia activation and pain behaviors following nerve injury-induced neuropathic pain. A spinal nerve transection (SNT) experimental model was used to induce neuropathic pain in mice. As a result of the peripheral nerve injury, SNT induced microgliosis and astrogliosis in the spinal cord, and upregulated inflammatory signals in both wild-type (WT) and Arg2 knockout (KO) mice. Notably, inflammation increased significantly in the Arg2 KO group compared to the WT group. We also observed a more robust microgliosis and a lower mechanical threshold in the Arg2 KO group than those in the WT group. Furthermore, our data revealed a stronger upregulation of M1 pro-inflammatory cytokines, such as interleukin (IL)-1β, and a stronger downregulation of M2 anti-inflammatory cytokines, including IL4 and IL-10, in Arg2 KO mice. Additionally, stronger formation of enzyme-inducible nitric oxide synthase, oxidative stress, and decreased expression of CD206 were detected in the Arg2 KO group compared to the WT group. These results suggest that Arg2 deficiency contributes to inflammatory response. The reduction or the loss of Arg2 results in the stronger neuroinflammation in the spinal dorsal horn, followed by more severe pain behaviors arising from nerve injury-induced neuropathic pain.

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Microglia in Pain: Detrimental and Protective Roles in Pathogenesis and Resolution of Pain

Cited by 578 publications

References 246 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

Frontline Science: Blood-circulating leukocytes fail to infiltrate the spinal cord parenchyma after spared nerve injury

Arginase 2 Deficiency Promotes Neuroinflammation and Pain Behaviors Following Nerve Injury in Mice

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