Up-Regulation of P2X<sub>4</sub>Receptors in Spinal Microglia after Peripheral Nerve Injury Mediates BDNF Release and Neuropathic Pain

Ulmann, Lauriane; Hatcher, Jon P.; Hughes, Jane P.; Chaumont, Séverine; Green, Paula J.; Conquet, François; Buell, Gary; Reeve, Alya; Chessell, Iain P.; Rassendren, François

doi:10.1523/jneurosci.2308-08.2008

Cited by 477 publications

(511 citation statements)

References 29 publications

(35 reference statements)

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“…It was shown that PNI‐induced pain hypersensitivity depends on ongoing purinergic signaling through microglial P2X4Rs. A marked reduction in neuropathic pain in both mice knocked down and knocked out of P2X4R further demonstrated the necessity of P2X4Rs51, 52, 53. Intrathecal delivery of P2X4R‐stimulated microglia caused normal rats to produce allodynia, indicating the sufficiency of P2X4R14, 51.…”

Section: Spinal Microglia Are Crucial For Neuropathic Painmentioning

confidence: 88%

“…It was shown that activation of microglial P2X4Rs stimulates the synthesis and release of brain‐derived neurotrophic factor (BDNF)52, 57, and that BDNF then causes an alteration of transmembrane anion gradient in a subpopulation of dorsal horn lamina I neurons presumably through the downregulation of the neuronal chloride transporter, KCC2, which in turn renders γ‐aminobutyric acid and glycine effects depolarizing, rather than hyperpolarizing, in these neurons (Figure 3). Furthermore, Keller et al 58.…”

Section: Spinal Microglia Are Crucial For Neuropathic Painmentioning

confidence: 99%

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Microglia in the spinal cord and neuropathic pain

Tsuda

2015

J of Diabetes Invest

197

147

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In contrast to physiological pain, pathological pain is not dependent on the presence of tissue‐damaging stimuli. One type of pathological pain – neuropathic pain – is often a consequence of nerve injury or of diseases such as diabetes. Neuropathic pain can be agonizing, can persist over long periods and is often resistant to known painkillers. A growing body of evidence shows that many pathological processes within the central nervous system are mediated by complex interactions between neurons and glial cells. In the case of painful peripheral neuropathy, spinal microglia react and undergo a series of changes that directly influence the establishment of neuropathic pain states. After nerve damage, purinergic P2X4 receptors (non‐selective cation channels activated by extracellular adenosine triphosphate) are upregulated in spinal microglia in a manner that depends on the transcription factors interferon regulatory factor 8 and 5, both of which are expressed in microglia after peripheral nerve injury. P2X4 receptor expression on the cell surface of microglia is also regulated at the post‐translational level by signaling from CC chemokine receptor chemotactic cytokine receptor 2. Furthermore, spinal microglia in response to extracellular stimuli results in signal transduction through intracellular signaling cascades, such as mitogen‐activated protein kinases, p38 and extracellular signal‐regulated protein kinase. Importantly, inhibiting the function or expression of these microglial molecules suppresses the aberrant excitability of dorsal horn neurons and neuropathic pain. These findings show that spinal microglia are a central player in mechanisms for neuropathic pain, and might be a potential target for treating the chronic pain state.

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Section: Spinal Microglia Are Crucial For Neuropathic Painmentioning

confidence: 88%

Section: Spinal Microglia Are Crucial For Neuropathic Painmentioning

confidence: 99%

Microglia in the spinal cord and neuropathic pain

Tsuda

2015

J of Diabetes Invest

197

147

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“…Additionally, P2X4 appears to play a crucial role in contributing to neuropathic pain [15,28,30] and P2X4 expression reflects the inflammation response during EAE [17]. Up-regulation of P2X4 expression was also detected in microglial cells at 7 days in a 3-day old rat's hypoxia-ischemia model [22], but the expression changes of P2X4 with time after hypoxia in P0 rats in AMC have remained to be fully clarified.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia induced amoeboid microglial cell activation in postnatal rat brain is mediated by ATP receptor P2X4

Wang

et al. 2011

BMC Neurosci

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BackgroundActivation of amoeboid microglial cells (AMC) and its related inflammatory response have been linked to the periventricular white matter damage after hypoxia in neonatal brain. Hypoxia increases free ATP in the brain and then induces various effects through ATP receptors. The present study explored the possible mechanism in ATP induced AMC activation in hypoxia.ResultsWe first examined the immunoexpression of P2X4, P2X7 and P2Y12 in the corpus callosum (CC) and subependyma associated with the lateral ventricles where both areas are rich in AMC. Among the three purinergic receptors, P2X4 was most intensely expressed. By double immunofluorescence, P2X4 was specifically localized in AMC (from P0 to P7) but the immunofluorescence in AMC was progressively diminished with advancing age (P14). It was further shown that P2X4 expression was noticeably enhanced in P0 day rats subjected to hypoxia and killed at 4, 24, 72 h and 7 d versus their matching controls by double labeling and western blotting analysis. P2X4 expression was most intense at 7 d whence the inflammatory response was drastic after hypoxia. We then studied the association of P2X4 with cytokine release in AMC after hypoxic exposure. In primary microglial cells exposed to hypoxia, IL-1β and TNF-α protein levels were up-regulated. Blockade of P2X4 receptor with 2', 3'-0-(2, 4, 6-Trinitrophenyl) adenosine 5'-triphosphate, a selective P2X1-7 blocker resulted in partial suppression of IL-1β (24% vs hypoxic group) and TNF-α expression (40% vs hypoxic group). However, pyridoxal phosphate-6-azo (benzene-2, 4-disulfonic acid) tetrasodium salt hydrate, a selective P2X1-3, 5-7 blocker did not exert any significant effect on the cytokine expression.ConclusionsIt is concluded that P2X4 which is constitutively expressed by AMC in postnatal rats was enhanced in hypoxia. Hypoxia induced increase in IL-1β and TNF-α expression was reversed by 2', 3'-0-(2, 4, 6-Trinitrophenyl) adenosine 5'-triphosphate suggesting that P2X4 mediates ATP induced AMC activation and its production of proinflammatory cytokines.

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“…Increased intracellular calcium levels induce, or increase, numerous signalling cascades leading to increased pro-inflammatory cytokine synthesis and secretion, as well as secretion of numerous other pro-inflammatory molecules. Indeed, using P2X 4 gene-deleted mice, Ulmann et al [39] have very recently shown that this mechanism comes into play in activated microglia via the release of brain-derived neurotrophic factor. Macrophages become increasingly activated by brainderived neurotrophic factor and other inflammatory molecules and this, in turn, likely leads to down-regulation of functional P2X 4 R. How this occurs remains to be determined but classical activation is known to markedly increase membrane turnover due to increased uptake of antigen for loading onto MHC Class II molecules [32,33,37].…”

Section: Discussionmentioning

confidence: 99%

Dynamic regulation of the P2X₄ receptor in alveolar macrophages by phagocytosis and classical activation

Stokes

Surprenant

2009

Eur J Immunol

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ATP-gated P2X 4 receptors (P2X 4 R) in macrophages and microglia have been implicated in neuropathic and inflammatory pain by currently unidentified mechanisms. P2X 4 R are found predominantly in intracellular lysosomal compartments but can be rapidly trafficked to the surface membrane by procedures that induce endolysosomal secretion. We studied total and surface membrane P2X 4 R protein expression by Western blot and biotinylation assays and functional expression by whole-cell patch clamp assays in human and rat alveolar macrophages in response to phagocytosis of zymosan and opsonized zymosan bioparticles and to classical and alternative macrophage activation. Unstimulated macrophages showed high total protein expression but very low functional expression. Phagocytosis rapidly (within 4 h) increased functional P2X 4 R expression by 2-to 7-fold as did chloroquine, an agent known to induce lysosomal secretion. In contrast, classical activation of macrophage for 48 h with IFN-c and TNF-a or IFN-c and LPS reduced surface and functional P2X 4 R expression by 3-fold without altering total P2X 4 R protein levels. Alternative activation with IL-4 or IL-13 did not alter total, surface or functional expression of P2X 4 R. This is the first study of the regulation of P2X 4 R in macrophages by physiological stimuli and presents a picture whereby P2X 4 R become functional in response to initial phagocytic stimuli but return to a non-functional state during sustained activation by classical macrophage activation.Key words: Inflammation . Ion channels . Patch-clamp . Purine receptors Introduction Extracellular ATP acts as a ''danger signal'' when it is released from cells during tissue damage and inflammation; it acts on metabotropic (G-protein coupled) P2Y and ionotropic (cation channel) P2X purinergic receptors to affect several inflammatory and immune responses [1,2]. There are seven members of the P2X receptor family (P2X 1-7 R) that show widespread distribution in both neuronal and non-neuronal tissues [3]. Two of these seven members, P2X 4 R and P2X 7 R, have generated increasing interest as potential anti-inflammatory drug targets [2,4,5]. The case for P2X 7 R is now well established: Stimulation of P2X 7 R in activated monocytes, macrophages and microglia leads to rapid release of pro-inflammatory IL-1b and IL-18 cytokines, to phospholipase D activation and, if stimulation is sustained, to apopotosis [1,[3][4][5]. Classical activation of macrophages, generally induced by IFN-g and/or LPS, up-regulates P2X 7 R mRNA and protein levels and functional expression [6,7] and this correlates well with a role for P2X 7 R in bacterial killing [8,9]. Recently, highly selective and potent P2X 7 R antagonists have been identified [10] with one of these showing initial positive results in Phase II clinical trials for rheumatoid arthritis [11]. The case for P2X 4 R remains tentative, largely due to the absence of selective P2X 4 R antagonists and the complicating presence of P2X 7 R, which is generally co-expressed with P2X 4 R in ...

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Up-Regulation of P2X₄Receptors in Spinal Microglia after Peripheral Nerve Injury Mediates BDNF Release and Neuropathic Pain

Cited by 477 publications

References 29 publications

Microglia in the spinal cord and neuropathic pain

Microglia in the spinal cord and neuropathic pain

Hypoxia induced amoeboid microglial cell activation in postnatal rat brain is mediated by ATP receptor P2X4

Dynamic regulation of the P2X₄ receptor in alveolar macrophages by phagocytosis and classical activation

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Up-Regulation of P2X4Receptors in Spinal Microglia after Peripheral Nerve Injury Mediates BDNF Release and Neuropathic Pain

Cited by 477 publications

References 29 publications

Microglia in the spinal cord and neuropathic pain

Microglia in the spinal cord and neuropathic pain

Hypoxia induced amoeboid microglial cell activation in postnatal rat brain is mediated by ATP receptor P2X4

Dynamic regulation of the P2X4 receptor in alveolar macrophages by phagocytosis and classical activation

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Up-Regulation of P2X₄Receptors in Spinal Microglia after Peripheral Nerve Injury Mediates BDNF Release and Neuropathic Pain

Dynamic regulation of the P2X₄ receptor in alveolar macrophages by phagocytosis and classical activation