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

• Published in: Brain, behavior, and immunity Vol. 48; pp. 222 - 231
• Main Authors: Benson, Sven, Rebernik, Laura, Wegner, Alexander, Kleine-Borgmann, Julian, Engler, Harald, Schlamann, Marc, Forsting, Michael, Schedlowski, Manfred, Elsenbruch, Sigrid
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.08.2015
• Subjects: Adult; Allergy and Immunology; Body Temperature - drug effects; Brain; Brain imaging; Central pain amplification; Cytokines; Double-Blind Method; Endotoxemia - blood; Endotoxemia - physiopathology; Experimental endotoxemia; Humans; Hydrocortisone - blood; Inflammation - blood; Inflammation - physiopathology; Interleukin-6 - blood; Lipopolysaccharide; Lipopolysaccharides; LPS; Magnetic Resonance Imaging; Male; Neural mechanisms; Pain - blood; Pain - physiopathology; Pain Measurement; Pain Threshold - physiology; Psychiatry; Tumor Necrosis Factor-alpha - blood; Visceral pain; Central pain amplification; Visceral pain; Brain imaging; Cytokines; Neural mechanisms; Experimental endotoxemia; Lipopolysaccharide; LPS
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2015.03.017

•We tested if experimental endotoxemia involves altered central pain processing.•BOLD responses within pain-related brain regions were enhanced during endotoxemia.•Cytokine responses correlated with pain-induced neural activation.•Peripheral inflammatory processes may contribute to human visceral hyperalgesia. 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, 0.4ng/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 6h post-injection. At baseline and 2h 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.