Neural circuitry mediating inflammation-induced central pain amplification in human experimental endotoxemia

Brain Behav Immun. 2015 Aug:48:222-31. doi: 10.1016/j.bbi.2015.03.017. Epub 2015 Apr 14.


Background & aims: To elucidate the brain mechanisms underlying inflammation-induced visceral hyperalgesia in humans, in this functional magnetic resonance imaging (fMRI) study we tested if intravenous administration of lipopolysaccharide (LPS) involves altered central processing of visceral pain stimuli.

Methods: In this randomized, double-blind, placebo-controlled fMRI study, 26 healthy male subjects received either an intravenous injection of low-dose LPS (N=14, 0.4 ng/kg body weight) or placebo (N=12, control group). Plasma cytokines (TNF-α, IL-6), body temperature, plasma cortisol and mood were assessed at baseline and up to 6 h post-injection. At baseline and 2 h post-injection (test), rectal pain thresholds and painful rectal distension-induced blood oxygen level-dependent (BOLD) responses in brain regions-of-interest were assessed. To address specificity for visceral pain, BOLD responses to non-painful rectal distensions and painful somatic stimuli (i.e., punctuate mechanical stimulation) were also analyzed as control stimuli.

Results: Compared to the control group, LPS-treated subjects demonstrated significant and transient increases in TNF-α, IL-6, body temperature and cortisol, along with impaired mood. In response to LPS, rectal pain thresholds decreased in trend, along with enhanced up-regulation of rectal pain-induced BOLD responses within the posterior insula, dorsolateral prefrontal (DLPFC), anterior midcingulate (aMCC) and somatosensory cortices (all FWE-corrected p<0.05). Within the LPS group, more pronounced cytokine responses correlated significantly with enhanced rectal pain-induced neural activation in DLPFC and aMCC. No significant LPS effects were observed on neural responses to non-painful rectal distensions or mechanical stimulation.

Conclusions: These findings support that peripheral inflammatory processes affect visceral pain thresholds and the central processing of sensory-discriminative aspects of visceral pain.

Keywords: Brain imaging; Central pain amplification; Cytokines; Experimental endotoxemia; LPS; Lipopolysaccharide; Neural mechanisms; Visceral pain.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Body Temperature / drug effects
  • Brain
  • Double-Blind Method
  • Endotoxemia / blood
  • Endotoxemia / physiopathology*
  • Humans
  • Hydrocortisone / blood
  • Inflammation / blood
  • Inflammation / physiopathology*
  • Interleukin-6 / blood
  • Lipopolysaccharides
  • Magnetic Resonance Imaging
  • Male
  • Pain / blood
  • Pain / physiopathology*
  • Pain Measurement
  • Pain Threshold / physiology
  • Tumor Necrosis Factor-alpha / blood


  • Interleukin-6
  • Lipopolysaccharides
  • Tumor Necrosis Factor-alpha
  • Hydrocortisone