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The Journal of Neuroscience, February 18, 2004, 24(7):1637-1645; doi:10.1523/JNEUROSCI.3118-03.2004

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Behavioral/Systems/Cognitive
Specific Inhibition of IB Kinase Reduces Hyperalgesia in Inflammatory and Neuropathic Pain Models in Rats

Irmgard Tegeder,^1 * Ellen Niederberger,^1 * Ronald Schmidt,¹ Susanne Kunz,¹ Hans Gühring,² Olaf Ritzeler,² Martin Michaelis,² and Gerd Geisslinger¹

¹pharmazentrum frankfurt, Institut für Klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, 60590 Frankfurt, Germany, and ²Aventis Pharma Deutschland, 65929 Frankfurt am Main, Germany

Phosphorylation of IB through IB kinase (IKK) is the first step in nuclear factor B (NF-B) activation and upregulation of NF-B-responsive genes. Hence, inhibition of IKK activity may be expected to prevent injury-, infection-, or stress-induced upregulation of various proinflammatory genes and may thereby reduce hyperalgesia and inflammation. In the present study, we tested this hypothesis using a specific and potent IKK inhibitor (S1627). In an IKK assay, S1627 inhibited IKK activity with an IC₅₀ value of 10.0 ± 1.2 nM. In cell culture experiments, S1627 inhibited interleukin (IL)-1-stimulated nuclear translocation and DNA-binding of NF-B. Plasma concentration time courses after intraperitoneal injection revealed a short half-life of 2.8 hr in rats. Repeated intraperitoneal injections were, therefore, chosen as the dosing regimen. S1627 reversed thermal and mechanical hyperalgesia at 3x 30 mg/kg in the zymosan-induced paw inflammation model and reduced the inflammatory paw edema at 3x 40 mg/kg. S1627 also significantly reduced tactile and cold allodynia in the chronic constriction injury model of neuropathic pain at 30 mg/kg once daily. The drug had no effect on acute inflammatory nociception in the formalin test and did not affect responses to heat and tactile stimuli in naive animals. As hypothesized, S1627 prevented the zymosan-induced nuclear translocation of NF-B in the spinal cord and the upregulation of NF-B-responsive genes including cyclooxygenase-2, tumor necrosis factor-, and IL-1. Our data indicate that IKK may prove an interesting novel drug target in the treatment of pathological pain and inflammation.

Key words: behavior; dorsal horn; hyperalgesia; neuropathy; protein kinase; transcription

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Received June 28, 2003; revised December 15, 2003; accepted December 17, 2003.

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