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October 26, 2005
9:00:00 AM - 11:00:00 AM
Hall C4
Attenuation of Astroglial-NF-kB Activation Reduces Formalin Pain Behavior
Eugene S. Fu, M.D., Yan P. Zhang, Ph.D., Zongqi Yang, M.D., Jacqueline Sagen, Ph.D., John R. Bethea, Ph.D.
Anesthesiology, University of Miami, Miami, Florida, United States
Introduction: In the central nervous system (CNS) the transcription factor NF-kB is a key regulator of inflammation and secondary injury processes. Following trauma or disease, the expression of NF-kB-dependent genes is highly activated, leading to both protective and detrimental effects on CNS recovery. A consequence of injury or disease to the nervous system is the development of pain. In the present work, we demonstrate that selective inactivation of the classical NF-kB activation pathway by inhibitory protein IkBα in astrocytes leads to a reduction in formalin-induced pain behavior.

Methods: Formalin testing was done on 25-30 g adult male wild type and transgenic C57Bl/6 mice. The experimental groups (n=8-15 per group) included wild type controls (WT) and GFAP-IkBαdn transgenic (TG) mice. The TG mice overexpress a dominant negative form of IkBα under the control of the GFAP promoter. Twenty µl of 5% formalin was injected into the left hindpaw, producing a paw licking behavior that was observed for up to 100 minutes. Formalin behavior was assessed by measuring the duration of left hindpaw licking in seconds. Two hours after formalin injection, animals underwent saline perfusion and spinal cord specimens (L4-5) were removed and fixed for c-Fos immunhistochemistry. Fos-like immunoreactive positive neurons were quantified microscopically in superficial (laminae I-II,) and deep (laminae III-VI) regions of the dorsal horn. Data were expressed as mean ± sem and analyzed using the GraphPad Prism software. An intergroup comparison of formalin behavior was performed with a one-way ANOVA. Expression for c-Fos was compared with an unpaired t-test.

Results: Paw licking behavior was observed in three phases. Phase I was measured at 0-10 min while Phase II was measured at 10-50 min. Phase III behavior continued after 50 min. Differences in paw-licking duration were observed between WT and TG mice in Phase II and Phase III, p<0.05 (figure1). Differences in c-Fos expression were observed between the formalin injected left hindpaw and the non-injected right hindpaw, p<0.05 (figure2). No differences in c-Fos expression were observed between WT and TG mice.

Conclusions: Phase II and Phase III formalin responses, which reflect central sensitization of pain, were lower in the GFAP-IkBαdn mice. Interestingly, there was no reduction in c-Fos expression in the TG mice, which is consistent with a previous finding seen in µ-opioid receptor knockout mice.1 Further studies utilizing other pain models involving nerve inflammation and injury are warranted to assess the role of astroglial NF-kB modulation in pain transmission.

1. Exp Neurol. 2003;184, 839-45[figure1][figure2]

Anesthesiology 2005; 103: A1092
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