IL-1ra alleviates inflammatory hyperalgesia through preventing phosphorylation of NMDA receptor NR-1 subunit in rats.
Although it has been shown that pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) facilitate perception of noxious inputs at the spinal level, the mechanisms have not been understood. This study determined the cell type that produces IL-1beta, the co-localization of IL-1 receptor type I (IL-1RI) and Fos and NR1 in the spinal cord, and the effects of IL-1 receptor antagonist (IL-1ra) on NR1 phosphorylation and hyperalgesia in a rat model of inflammatory pain. Phosphorylation of NR1, an essential subunit of the NMDA receptor (NMDAR), is known to modulate NMDAR activity and facilitate pain. Hyperalgesia was induced by injecting complete Freund's adjuvant (CFA, 0.08ml, 40microg Mycobacterium tuberculosis) into one hind paw of each rat. Paw withdrawal latency (PWL) was tested before CFA (-48h) for baseline and 2 and 24h after CFA to assess hyperalgesia. IL-1ra was given (i.t.) 24h before CFA to block the action of basal IL-1beta and 2h prior to each of two PWL tests to block CFA-induced IL-1beta. Spinal cords were removed for double immunostaining of IL-1beta/neuronal marker and IL-1beta/glial cell markers, IL-1RI/Fos and IL-1RI/NR1, and for Western blot to measure NR1 phosphorylation. The data showed that: (1) astrocytes produce IL-1beta, (2) IL-1RI is localized in Fos- and NR1-immunoreactive neurons within the spinal dorsal horn, and (3) IL-1ra at 0.01mg/rat significantly increased PWL (P<0.05) and inhibited NR1 phosphorylation compared to saline control. The results suggest that spinal IL-1beta is produced by astrocytes and enhances NR1 phosphorylation to facilitate inflammatory pain.
Zhang
Rui-Xin
RX
Center for Integrative Medicine, School of Medicine, University of Maryland, Baltimore, MD 21201, USA Department of Biomedical Sciences, Dental School, University of Maryland, Baltimore, MD 21201, USA.
Li
Aihui
A
Liu
Bing
B
Wang
Linbo
L
Ren
Ke
K
Zhang
Haiqing
H
Berman
Brian M
BM
Lao
Lixing
L
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D005911:Gliosis / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D006930:Hyperalgesia / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000276:immunology; D008297:Male; D010146:Pain / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000276:immunology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism
D000700:Analgesics; D000893:Anti-Inflammatory Agents; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; C409466:NR1 NMDA receptor; D016760:Proto-Oncogene Proteins c-fos; D017472:Receptors, Interleukin-1; D016194:Receptors, N-Methyl-D-Aspartate
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