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Variability in the Analgesic Response to Ibuprofen Following Third Molar Extraction is Associated with Differences in Activation of the Cyclooxygenase Pathway

ABSTRACT: It has long been recognized that there is substantial inter-individual variability in the analgesic efficacy of non-steroidal anti-inflammatory drugs (NSAIDs), but the mechanisms underlying this variability are not well understood. In order to characterize the factors associated with heterogeneity in response to ibuprofen, we performed functional neuroimaging, pharmacokinetic/pharmacodynamic assessments, biochemical assays, and gene expression analysis in twenty-nine healthy subjects who underwent third molar extraction. Subjects were treated with rapid-acting ibuprofen (400 mg; N=19) or placebo (N=10) in a randomized, double-blind design. Compared to placebo, ibuprofen-treated subjects exhibited greater reduction in pain scores, alterations in CBF in brain regions associated with pain processing, and inhibition of ex vivo COX-1 and COX-2 activity and urinary prostaglandin metabolites (p<0.05). Ibuprofen-treated subjects could be stratified into partial responders (N=9, required rescue medication) and complete responders (N=10, no rescue medication). This variability in analgesic efficacy was not associated with demographic/clinical characteristics, markers of systemic inflammation, or ibuprofen pharmacokinetics. Complete responders exhibited less suppression of urinary prostaglandin metabolites and greater induction of serum tumor necrosis factor-α and interleukin 8, compared to partial responders (p<0.05). Partial responders exhibited more alterations in gene expression in peripheral blood mononuclear cells after surgery, with an enrichment in inflammatory pathways. These findings suggest that activation of the prostanoid biosynthetic pathway and regulation of the inflammatory response to surgery differs between partial and complete responders. Future studies are necessary to elucidate the molecular mechanisms underlying this variability and identify biomarkers that are predictive of ibuprofen response.

ORGANISM(S): Homo sapiens

PROVIDER: GSE120596 | GEO | 2019/04/02

REPOSITORIES: GEO

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Project description:The electroacupuncture-induced analgesic effect has been used widely to alleviate diverse pains. However, significant individual variations in analgesic effect of EA for both experiments and clinics were reported. According to the sensitivity of the analgesic response to EA stimulation, the subjects could be categorized into high responders (HR) and low responders (LR). However, the molecular mechanism of individual variability in the analgesic response to acupuncture stimulation is still uncertain. This study aims to investigate the potential gene expression in spinal dorsal horn induced by 2Hz/100Hz electroacupuncture in HR and LR rats. Rats were given 2Hz or 100Hz electroacupuncture for 30 min and using cDNA microarrays to compare different gene expression in dorsal horn. Transcriptome profiling analysis found that some co-regulated genes related with electroacupuncture or 2Hz or 100Hz freqencies. These co-regulated genes were plasticity-related by GO analysis. We also found some special regulated genes in HR vs. LR in 2Hz/100Hz electroacupuncture stimulation. These results suggested that neurotransmitter system and cytokine different between HR with LR in 2Hz electroacupuncture. But in 100Hz electroacupunture, there were many different regulated genes related with ribosome between HR with LR, which needs more studies to research the function and may play an important role in HR vs. LR by 100Hz electroacupuncture. Keywords: Transcriptome analysis Rats were exposed to different frequencies (2Hz or 100Hz) electroacupuncture stimlation for 30 min and nociceptive testing and returned to home cages for 1 hours before sacrificed. According to the sensitivity of the analgesic response to 2Hz or 100Hz EA stimulation, the rats divided into four groups: 2Hz-HR group, 2Hz-LR group, 100Hz-HR group and 100Hz-LR group. Subsequently analyzed their dorsal horn transcript profile using cDNA microarrays, the rats were without receiving electroacupuncture as control. The tissue of dorsal horn (DH) of the fifth and sixth lumbar (L5 and L6) of four or five rats were selected for transcript analysis in each group. The five control rats were mixed and labeled with cy5, each rat of experiment groups was labeled with cy3.

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Variability in the Analgesic Response to Ibuprofen Following Third Molar Extraction is Associated with Differences in Activation of the Cyclooxygenase Pathway

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