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 pPKCgamma 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 96h after CFA the NR1 KO mice are no longer protected from allodynia and the SCDH expression of pPKCgamma and pERK2 are increased. At 96h the expression of the proinflammatory cytokine, IL-1beta, and pERK2 are increased in astrocytes. Intrathecal IL-1 receptor antagonist (IL-1ra), acting on neuronal IL-1 receptors, completely reverses the allodynia at 96h after CFA. Deletion of NMDAR-dependent signaling in neurons protects against early CFA-induced allodynia. Subsequent NMDAR-independent signaling that involves neuronal expression of pPKCgamma and the induction of pERK2 and IL-1beta in activated astrocytes contributes to the emergence of NMDAR-independent inflammatory pain behavior at 96h after CFA. Effective reduction of the initiation and maintenance of inflammatory pain requires targeting the neuron-astrocyte-cytokine interactions revealed in these studies.
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA Department of Neurology and the Pain and Palliative Care Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Weyerbacher
authors.forename: Qinghao
authors.initials: Q
authors.lastname: Xu
authors.forename: Cristina
authors.initials: C
authors.lastname: Tamasdan
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Shin
authors.forename: Charles E
authors.initials: CE
authors.lastname: Inturrisi
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology; D001253:Astrocytes / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005620:Freund's Adjuvant; D007839:Functional Laterality; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D007249:Inflammation / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D048730:MAP Kinase Kinase Kinase 2 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D010146:Pain / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D017288:Pain Threshold / Q000502:physiology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000172:deficiency / Q000502:physiology*; D013116:Spinal Cord / Q000473:pathology; D013997:Time Factors
chemical_list: D018501:Antirheumatic Agents; D005904:Glial Fibrillary Acidic Protein; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D049452:Green Fluorescent Proteins; D005620:Freund's Adjuvant; D011493:Protein Kinase C; D048730:MAP Kinase Kinase Kinase 2; D010751:Phosphopyruvate Hydratase