title: Neural circuitry mediating inflammation-induced central pain amplification in human experimental endotoxemia.
abstract: OBJECTIVE
  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.
authors.affiliation: Institute of Medical Psychology & Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, D-45147 Essen, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Benson
authors.affiliation: Institute of Medical Psychology & Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, D-45147 Essen, Germany; Institute of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University of Duisburg-Essen, D-45147 Essen, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Rebernik
authors.affiliation: Clinic for Trauma Surgery, University Hospital Essen, University of Duisburg-Essen, D-45147 Essen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Wegner
authors.affiliation: Institute of Medical Psychology & Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, D-45147 Essen, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Kleine-Borgmann
authors.affiliation: Institute of Medical Psychology & Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, D-45147 Essen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Engler
authors.affiliation: Institute of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University of Duisburg-Essen, D-45147 Essen, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Schlamann
authors.affiliation: Institute of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University of Duisburg-Essen, D-45147 Essen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Forsting
authors.affiliation: Institute of Medical Psychology & Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, D-45147 Essen, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Schedlowski
authors.affiliation: Institute of Medical Psychology & Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, D-45147 Essen, Germany. Electronic address: sigrid.elsenbruch@uk-essen.de.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Elsenbruch
mesh_terms: D000328:Adult; D001831:Body Temperature / Q000187:drug effects; D001921:Brain; D004311:Double-Blind Method; D019446:Endotoxemia / Q000097:blood / Q000503:physiopathology*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007249:Inflammation / Q000097:blood / Q000503:physiopathology*; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides; D008279:Magnetic Resonance Imaging; D008297:Male; D010146:Pain / Q000097:blood / Q000503:physiopathology*; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D006854:Hydrocortisone
keywords: Brain imaging; Central pain amplification; Cytokines; Experimental endotoxemia; LPS; Lipopolysaccharide; Neural mechanisms; Visceral pain