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The Journal of Neuroscience, October 14, 2009, 29(41):12919-12929; doi:10.1523/JNEUROSCI.1496-09.2009

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Cellular/Molecular
Inhibitor B Kinase β Deficiency in Primary Nociceptive Neurons Increases TRP Channel Sensitivity

Vanessa Bockhart,^1 * Cristina Elena Constantin,^3 * Annett Häussler,¹ Nina Wijnvoord,¹ Maike Kanngiesser,¹ Thekla Myrczek,¹ Geethanjali Pickert,¹ Laura Popp,¹ Jürgen-Markus Sobotzik,² Manolis Pasparakis,⁴ Rohini Kuner,⁵ Gerd Geisslinger,¹ Christian Schultz,² Michaela Kress,³ and Irmgard Tegeder¹

¹pharmazentrum frankfurt, Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit (ZAFES), Department of Clinical Pharmacology, and ²Department of Clinical Neuroanatomy, Goethe University, 60590 Frankfurt, Germany, ³Department of Physiology, University of Innsbruck, A-6020 Innsbruck, Austria, ⁴Institute for Genetics, University of Cologne, 50674 Cologne, Germany, and ⁵Department of Pharmacology, University of Heidelberg, 69120 Heidelberg, Germany

Correspondence should be addressed to Irmgard Tegeder, pharmazentrum frankfurt, Institut für Klinische Pharmakologie, Klinikum der Goethe Universität Frankfurt, Theodor Stern Kai 7, Haus 74, Raum 4.101a, 60590 Frankfurt am Main, Germany. Email: tegeder{at}em.uni-frankfurt.de

Inhibitor B kinase (IKK) regulates the activity of the transcription factor nuclear factor- B that normally protects neurons against excitotoxicity. Constitutively active IKK is enriched at axon initial segments and nodes of Ranvier (NR). We used mice with a Cre–loxP-mediated specific deletion of IKKβ in sensory neurons of the dorsal root ganglion (SNS–IKKβ^–/–) to evaluate whether IKK plays a role in sensory neuron excitability and nociception. We observed increased sensitivity to mechanical, cold, noxious heat and chemical stimulation in SNS–IKKβ^–/– mice, with normal proprioceptive and motor functions as revealed by gait analysis. This was associated with increased calcium influx and increased inward currents in small- and medium-sized primary sensory neurons of SNS–IKKβ^–/– mice during stimulation with capsaicin or Formalin, specific activators of transient receptor potentials TRPV1 and TRPA1 calcium channels, respectively. In vitro stimulation of saphenous nerve preparations of SNS–IKKβ^–/– mice showed increased neuronal excitability of A- and C-fibers but unchanged A- and C-fiber conduction velocities, normal voltage-gated sodium channel currents, and normal accumulation of ankyrin G and the sodium channels Nav1.6 at NR. The results suggest that IKKβ functions as a negative modulator of sensory neuron excitability, mediated at least in part by modulation of TRP channel sensitivity.

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Received March 30, 2009; revised July 11, 2009; accepted Aug. 12, 2009.

Correspondence should be addressed to Irmgard Tegeder, pharmazentrum frankfurt, Institut für Klinische Pharmakologie, Klinikum der Goethe Universität Frankfurt, Theodor Stern Kai 7, Haus 74, Raum 4.101a, 60590 Frankfurt am Main, Germany. Email: tegeder{at}em.uni-frankfurt.de

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