Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Tyrosine Kinase Inhibitors Reduce NMDA Receptor NR1 Expression, Nuclear Translocation and Thermal Hyperalgesia/CentralSensitization in a Rat Arthritis Model.
McNearney5, Terry A., Lu5, Ying, Ye2, Zaiming, Zhang3, Liping, Taglialatela5, Giulio, Pappas1, Todd, Zhang5, Wen-Ru
This study was designed determine if the central changes of the spinal cord in response to a peripheral inflammatory knee joint arthritis in rats are mediated by non-receptor tyrosine kinase.
Spinal microdialysis administration of non-receptor tyrosine kinase inhibitors was used to measure their impact on secondary thermal hyperalgesia upon application of noxious radiant heat to the ipsilateral footpad in a kaolin and carrageenan (k/c)-induced knee arthritis model. NMDA NR1 cellular expression and nuclear localization by immunocytochemistry and Western blot analysis of the lumbar spinal cord were also measured. Statistics: Student's t-tests and one-way ANOVA Newman Keuls Multiple Comparison tests. A p value <0.05 was considered significant.
Tyrosine kinase inhibitors genistein and lavendustin A, (but not lavendustin B or diadzein) effectively reduced 1) the development of secondary hyperalgesia, 2) the increases in glutamate NMDA receptor subunit NR1 expression in spinal cord that normally ensue 4 hours after intra-articular k/c-induced knee joint inflammation and 3) nuclear translocation of NR1. Genistein or staurosporin also inhibited the upregulation and shift of NMDA NR1 protein staining to the nuclear membrane and nucleus that is notable within 4 hours after treatment of neuroblastoma (SH-SY5Y) cell cultures with glutamate. Nuclear translocation of the NMDA NR1 subunit was also evident with activation of human primary and clonal synoviocytes. Nucleotide sequencing from clonal synoviocyte cDNA confirmed a putative nuclear localization sequence, similar to sequences derived from neuronal cells.
Tyrosine phosphorylation is necessary for spinal cord responses to peripheral inflammation including centrally mediated nociceptive sensitization producing secondary hyperalgesia. Tyrosine phosphorylation is required for NMDA receptor mediated NR1 subunit nuclear translocation, upregulation and perhaps other long term plastic changes. These studies implicate NR1 in direct interactions with the nucleus suggesting a role for NR1 as a fast intracellular mediator.
To cite this abstract, please use the following information:
McNearney, Terry A., Lu, Ying, Ye, Zaiming, Zhang, Liping, Taglialatela, Giulio, Pappas, Todd, et al; Tyrosine Kinase Inhibitors Reduce NMDA Receptor NR1 Expression, Nuclear Translocation and Thermal Hyperalgesia/CentralSensitization in a Rat Arthritis Model. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1536