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Inhibitor kappaB Kinase beta deficiency in primary nociceptive neurons increases TRP channel sensitivity

Vanessa Bockhart1, Cristina Elena Constantin, Annett Häussler

  • 1pharmazentrum frankfurt, Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit, Department of Clinical Pharmacology, Goethe University, 60590 Frankfurt, Germany.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|October 16, 2009
PubMed

Insights

Inhibitor kappaB kinase beta (IKKbeta) normally suppresses sensory neuron excitability. Deleting IKKbeta in sensory neurons increases pain sensitivity by enhancing TRP channel activity.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pain Research

Background:

  • Inhibitor kappaB kinase (IKK) regulates nuclear factor-kappa B (NF-κB) pathway, crucial for neuronal protection against excitotoxicity.
  • Constitutively active IKK is found at axon initial segments and nodes of Ranvier (NR).

Purpose of the Study:

  • To investigate the role of IKKbeta in sensory neuron excitability and nociception using a specific genetic deletion model.
  • To determine if IKKbeta modulates the function of transient receptor potential (TRP) channels in sensory neurons.

Main Methods:

  • Generated mice with a Cre-loxP-mediated deletion of IKKbeta specifically in dorsal root ganglion sensory neurons (SNS-IKKbeta(-/-)).
  • Assessed sensory functions (mechanical, cold, heat, chemical sensitivity) and motor functions (gait analysis).
  • Measured calcium influx and inward currents in primary sensory neurons and analyzed nerve fiber excitability and conduction velocity in vitro.

Main Results:

  • SNS-IKKbeta(-/-) mice exhibited heightened sensitivity to various stimuli, indicating increased nociception, without motor or proprioceptive deficits.
  • Increased calcium influx and inward currents were observed in sensory neurons upon stimulation of TRPV1 and TRPA1 channels.
  • In vitro studies revealed enhanced neuronal excitability in A- and C-fibers of SNS-IKKbeta(-/-) mice, with normal conduction velocities and sodium channel function at the NR.

Conclusions:

  • IKKbeta acts as a negative regulator of sensory neuron excitability.
  • This inhibitory role is, at least partly, mediated through the modulation of TRP channel sensitivity, impacting pain perception.

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