Inhibitor κB Kinase β Deficiency in Primary Nociceptive Neurons Increases TRP Channel Sensitivity

Abstract

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-loxPmediated specific deletion of IKK␤ in sensory neurons of the dorsal root ganglion (SNS-IKK␤ Ϫ/Ϫ ) 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-IKK␤ Ϫ/Ϫ 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-IKK␤ Ϫ/Ϫ 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-IKK␤ Ϫ/Ϫ 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 IKK␤ functions as a negative modulator of sensory neuron excitability, mediated at least in part by modulation of TRP channel sensitivity.

The Protein Kinase IKKε Is a Potential Target for the Treatment of Inflammatory Hyperalgesia

“…An inhibitor of the IKK subunit of the classical I-kB kinase complex provided similar anti-inflammatory properties as observed in the current study in IKKε KO mice or after pharmacological inhibition in WT mice (34,35). Furthermore, mice with a conditional KO of IKKb in sensory afferent neurons demonstrated somewhat decreased hyperalgesia in the second phase of the formalin assay (36). Because it was assumed that the classical complex is inflammation specific and almost free from substrates, apart from the NF-kB-activation pathway (5), it was hypothesized that it constitutes an ideal target for anti-inflammatory drugs.…”

Distinct Roles for JNK and IKK Activation in Agouti-Related Peptide Neurons in the Development of Obesity and Insulin Resistance

“…Activation of either inflammatory signaling branch results in increased firing of AgRP neurons. In fact, both JNK and IKK2 have been demonstrated to regulate glutamatergic signaling and synapse maturation, raising the possibility that both inflammatory kinases promote AgRP neuron excitability via similar or distinct pathways (Thomas et al, 2008;Bockhart et al, 2009;Ahn and Choe, 2010;Schmeisser et al, 2012). Interestingly, despite the fact that, in both models, AgRP firing is increased by $2-fold ( Figure S1I), only the AgRP JNK1CA mice develop obesity.…”

SNO-ing at the Nociceptive Synapse?

“…Depolarization or stimulation with glutamate leads to a redistribution of NF-B from neurites to the nucleus (Mikenberg et al, 2007) so that NF-B acts as a signal transducer, transmitting transient glutamatergic signals from distant synaptic sites to the nucleus (Kaltschmidt et al, 1994). In sensory neurons, constitutively active IKK regulates the activation threshold of TRP channels and dampens responses to acute nociceptive stimulation (Bockhart et al, 2009). Oxidative stress leads to activation of IKK and subsequent NF-B-mediated gene expression and NOS up-regulation.…”