Inhibitor kappa B kinase beta dependent cytokine upregulation in nociceptive neurons contributes to nociceptive hypersensitivity after sciatic nerve injury.

UNLABELLED: Inhibitor kappa B kinase (IKK)-mediated nuclear factor-kappa B (NF-κB) activation is a major pathway for transcriptional control of various pro-inflammatory factors. We here assessed whether activation of this pathway specifically in primary nociceptive neurons of the dorsal root ganglia (DRG) contributes to the development of nociceptive hypersensitivity. Mice carrying a cre-loxP-mediated deletion of inhibitor kappa B kinase beta (IKKß) in DRG neurons were protected from nerve injury-evoked allodynia and hyperalgesia. This effect was mimicked by systemic treatment with an IKKß inhibitor but was not observed upon specific inhibition of IKKß in the spinal cord, suggesting a specific role of IKKß in the peripheral neurons. The deletion of IKKß in DRG neurons did not affect constitutive neuronal NF-κB activity, but reduced nerve injury-evoked NF-κB stimulation in the DRG and was associated with reduced upregulation of interleukin-16, monocyte chemoattractant protein-1/chemokine (CC motif) ligand 2 (MCP-1/CCL2), and tumor necrosis factor alpha (TNFα) in the DRG. These cytokines evoked a rapid rise of intracellular calcium in subsets of primary DRG neurons. The results suggest that IKKß-mediated NF-κB stimulation in injured primary sensory neurons promotes cytokine and chemokine production and contributes thereby to the development of chronic pain. PERSPECTIVE: Inhibitors of IKK that do not pass the blood-brain barrier and act only in the periphery might be useful for reduction of the pro-inflammatory response in peripheral DRG neurons and reduce thereby nerve injury-evoked pain without affecting neuroprotective effects of NF-κB in the central nervous system.

Effect sizes in experimental pain produced by gender, genetic variants and sensitization procedures.

BACKGROUND: Various effects on pain have been reported with respect to their statistical significance, but a standardized measure of effect size has been rarely added. Such a measure would ease comparison of the magnitude of the effects across studies, for example the effect of gender on heat pain with the effect of a genetic variant on pressure pain. METHODOLOGY/PRINCIPAL FINDINGS: Effect sizes on pain thresholds to stimuli consisting of heat, cold, blunt pressure, punctuate pressure and electrical current, administered to 125 subjects, were analyzed for 29 common variants in eight human genes reportedly modulating pain, gender and sensitization procedures using capsaicin or menthol. The genotype explained 0-5.9% of the total interindividual variance in pain thresholds to various stimuli and produced mainly small effects (Cohen's d 0-1.8). The largest effect had the TRPA1 rs13255063T/rs11988795G haplotype explaining >5% of the variance in electrical pain thresholds and conferring lower pain sensitivity to homozygous carriers. Gender produced larger effect sizes than most variant alleles (1-14.8% explained variance, Cohen's d 0.2-0.8), with higher pain sensitivity in women than in men. Sensitization by capsaicin or menthol explained up to 63% of the total variance (4.7-62.8%) and produced largest effects according to Cohen's d (0.4-2.6), especially heat sensitization by capsaicin (Cohen's d = 2.6). CONCLUSIONS: Sensitization, gender and genetic variants produce effects on pain in the mentioned order of effect sizes. The present report may provide a basis for comparative discussions of factors influencing pain.