P2X4R+ Microglia Drive Neuropathic Pain

Overview

Journal Nat Neurosci

Date 2012 Jul 28

PMID 22837036

Citations 178

Authors

Simon Beggs

Tuan Trang

Michael W Salter

Affiliations

Soon will be listed here.

Abstract

Neuropathic pain, the most debilitating of all clinical pain syndromes, may be a consequence of trauma, infection or pathology from diseases that affect peripheral nerves. Here we provide a framework for understanding the spinal mechanisms of neuropathic pain as distinct from those of acute pain or inflammatory pain. Recent work suggests that a specific microglia response phenotype characterized by de novo expression of the purinergic receptor P2X4 is critical for the pathogenesis of pain hypersensitivity caused by injury to peripheral nerves. Stimulating P2X4 receptors initiates a core pain signaling pathway mediated by release of brain-derived neurotrophic factor, which produces a disinhibitory increase in intracellular chloride in nociceptive (pain-transmitting) neurons in the spinal dorsal horn. The changes caused by signaling from P2X4R(+) microglia to nociceptive transmission neurons may account for the main symptoms of neuropathic pain in humans, and they point to specific interventions to alleviate this debilitating condition.

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References

Coull J, Boudreau D, Bachand K, Prescott S, Nault F, Sik A . Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature. 2003; 424(6951):938-42. DOI: 10.1038/nature01868. View

Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter M . P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature. 2003; 424(6950):778-83. DOI: 10.1038/nature01786. View

Kreutzberg G . Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 1996; 19(8):312-8. DOI: 10.1016/0166-2236(96)10049-7. View

Abbadie C, Bhangoo S, De Koninck Y, Malcangio M, Melik-Parsadaniantz S, White F . Chemokines and pain mechanisms. Brain Res Rev. 2009; 60(1):125-34. PMC: 2691997. DOI: 10.1016/j.brainresrev.2008.12.002. View

Clark A, Gentry C, Bradbury E, McMahon S, Malcangio M . Role of spinal microglia in rat models of peripheral nerve injury and inflammation. Eur J Pain. 2006; 11(2):223-30. DOI: 10.1016/j.ejpain.2006.02.003. View

Asiedu M, Ossipov M, Kaila K, Price T . Acetazolamide and midazolam act synergistically to inhibit neuropathic pain. Pain. 2009; 148(2):302-308. PMC: 2914558. DOI: 10.1016/j.pain.2009.11.015. View

Ulmann L, Hatcher J, Hughes J, Chaumont S, Green P, Conquet F . Up-regulation of P2X4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain. J Neurosci. 2008; 28(44):11263-8. PMC: 6671487. DOI: 10.1523/JNEUROSCI.2308-08.2008. View

Suter M, Berta T, Gao Y, Decosterd I, Ji R . Large A-fiber activity is required for microglial proliferation and p38 MAPK activation in the spinal cord: different effects of resiniferatoxin and bupivacaine on spinal microglial changes after spared nerve injury. Mol Pain. 2009; 5:53. PMC: 2759920. DOI: 10.1186/1744-8069-5-53. View

Biber K, Tsuda M, Tozaki-Saitoh H, Tsukamoto K, Toyomitsu E, Masuda T . Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development. EMBO J. 2011; 30(9):1864-73. PMC: 3101996. DOI: 10.1038/emboj.2011.89. View

10.

Knabl J, Witschi R, Hosl K, Reinold H, Zeilhofer U, Ahmadi S . Reversal of pathological pain through specific spinal GABAA receptor subtypes. Nature. 2008; 451(7176):330-4. DOI: 10.1038/nature06493. View

11.

Prescott S, Sejnowski T, De Koninck Y . Reduction of anion reversal potential subverts the inhibitory control of firing rate in spinal lamina I neurons: towards a biophysical basis for neuropathic pain. Mol Pain. 2006; 2:32. PMC: 1624821. DOI: 10.1186/1744-8069-2-32. View

12.

Jahr C, Jessell T . ATP excites a subpopulation of rat dorsal horn neurones. Nature. 1983; 304(5928):730-3. DOI: 10.1038/304730a0. View

13.

Tsuda M, Masuda T, Kitano J, Shimoyama H, Tozaki-Saitoh H, Inoue K . IFN-gamma receptor signaling mediates spinal microglia activation driving neuropathic pain. Proc Natl Acad Sci U S A. 2009; 106(19):8032-7. PMC: 2683100. DOI: 10.1073/pnas.0810420106. View

14.

Tsuda M, Toyomitsu E, Komatsu T, Masuda T, Kunifusa E, Nasu-Tada K . Fibronectin/integrin system is involved in P2X(4) receptor upregulation in the spinal cord and neuropathic pain after nerve injury. Glia. 2008; 56(5):579-85. DOI: 10.1002/glia.20641. View

15.

de Jong E, Dijkstra I, Hensens M, Brouwer N, van Amerongen M, Liem R . Vesicle-mediated transport and release of CCL21 in endangered neurons: a possible explanation for microglia activation remote from a primary lesion. J Neurosci. 2005; 25(33):7548-57. PMC: 6725403. DOI: 10.1523/JNEUROSCI.1019-05.2005. View

16.

Foley J, McIver S, Haydon P . Gliotransmission modulates baseline mechanical nociception. Mol Pain. 2011; 7:93. PMC: 3248913. DOI: 10.1186/1744-8069-7-93. View

17.

Hanisch U, Kettenmann H . Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 2007; 10(11):1387-94. DOI: 10.1038/nn1997. View

18.

Lin T, Li K, Zhang F, Zhang Z, Light A, Fu K . Dissociation of spinal microglia morphological activation and peripheral inflammation in inflammatory pain models. J Neuroimmunol. 2007; 192(1-2):40-8. PMC: 2198900. DOI: 10.1016/j.jneuroim.2007.09.003. View

19.

Trang T, Beggs S, Wan X, Salter M . P2X4-receptor-mediated synthesis and release of brain-derived neurotrophic factor in microglia is dependent on calcium and p38-mitogen-activated protein kinase activation. J Neurosci. 2009; 29(11):3518-28. PMC: 3589565. DOI: 10.1523/JNEUROSCI.5714-08.2009. View

20.

Fam S, Gallagher C, Salter M . P2Y(1) purinoceptor-mediated Ca(2+) signaling and Ca(2+) wave propagation in dorsal spinal cord astrocytes. J Neurosci. 2001; 20(8):2800-8. PMC: 6772222. View