N-Methyl-d-aspartate receptor (NMDAR) independent maintenance of inflammatory pain Journal Article


Authors: Weyerbacher, A. R.; Xu, Q.; Tamasdan, C.; Shin, S. J.; Inturrisi, C. E.
Article Title: N-Methyl-d-aspartate receptor (NMDAR) independent maintenance of inflammatory pain
Abstract: Following peripheral inflammation, NMDA receptor (NMDAR) activation in spinal cord dorsal horn neurons facilitates the generation of pain in response to low threshold inputs (allodynia) and signals the phosphorylation of protein kinase C (pPKC) and extracellular signal-regulated kinase 2 (pERK2). Intraplantar complete Freund's adjuvant (CFA) induces inflammatory nociception (allodynic pain) at 24 hours (h) with a concurrent increase in neuronal pPKCγ and pERK2 but not glial pERK2. These effects are attenuated in a spatial knockout of the NMDAR (NR1 KO) confined to SCDH neurons. Although glia and proinflammatory cytokines are implicated in the maintenance of inflammatory pain and neuronal activation, the role of NMDARs and neuronal-glial-cytokine interactions that initiate and maintain inflammatory pain are not well defined. In the maintenance phase of inflammatory pain at 96 h after CFA the NR1 KO mice are no longer protected from allodynia and the SCDH expression of pPKCγ and pERK2 are increased. At 96 h the expression of the proinflammatory cytokine, IL-1β, and pERK2 are increased in astrocytes. Intrathecal IL-1 receptor antagonist (IL-1ra), acting on neuronal IL-1 receptors, completely reverses the allodynia at 96 h after CFA. Deletion of NMDAR-dependent signaling in neurons protects against early CFA-induced allodynia. Subsequent NMDAR-independent signaling that involves neuronal expression of pPKCγ and the induction of pERK2 and IL-1β in activated astrocytes contributes to the emergence of NMDAR-independent inflammatory pain behavior at 96 h after CFA. Effective reduction of the initiation and maintenance of inflammatory pain requires targeting the neuron-astrocyte-cytokine interactions revealed in these studies. © 2009 International Association for the Study of Pain.
Keywords: controlled study; protein expression; nonhuman; animal cell; mouse; animals; mice; animal tissue; pain; glial fibrillary acidic protein; animal experiment; animal model; astrocyte; inflammation; neurons; phosphorylation; mice, inbred c57bl; time factors; mice, transgenic; spinal cord; mitogen activated protein kinase 1; green fluorescent proteins; protein kinase c; disease models, animal; functional laterality; hyperalgesia; nociception; pain threshold; astrocytes; protein kinase c gamma; interleukin 1 receptor antagonist protein; gene expression regulation, enzymologic; allodynia; n methyl dextro aspartic acid receptor; interleukin-1beta; freund's adjuvant; erk2; inflammatory pain; interleukin-1β; nmda receptor; spinal cord dorsal horn; freund adjuvant; spinal cord nerve cell; antirheumatic agents; map kinase kinase kinase 2; phosphopyruvate hydratase; receptors, n-methyl-d-aspartate
Journal Title: Pain
Volume: 148
Issue: 2
ISSN: 0304-3959
Publisher: Elsevier Science BV  
Date Published: 2010-02-01
Start Page: 237
End Page: 246
Language: English
DOI: 10.1016/j.pain.2009.11.003
PUBMED: 20005044
PROVIDER: scopus
PMCID: PMC2831745
DOI/URL:
Notes: --- - "Cited By (since 1996): 5" - "Export Date: 20 April 2011" - "CODEN: PAIND" - "Source: Scopus"
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