Inflammation-induced hyperalgesia: Effects of timing,dosage, and negative affect on somatic pain sensitivity in human experimental endotoxemia |
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| Affiliation: | 1. FORWARD, The National Data Bank for Rheumatic Diseases, Wichita, KS, United States;2. University of Kansas School of Medicine, Wichita, KS, United States;3. Institute of Rheumatology, Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel;4. Department of Medicine, University of Kansas School of Medicine-Wichita, Wichita, KS, United States;5. Monash University and Monash Health, Melbourne, Australia;6. University of Nebraska Medical Center, Omaha, NE, United States;7. Faculty of Behavioral, Management and Social Sciences, University of Twente, Enschede, the Netherlands;8. National Institute of Nursing Research, National Institutes of Health, Bethesda, MD, United States;9. Department Internal Medicine 1, Klinikum Saarbrücken, Saarbrücken, Germany;10. Department Psychosomatic Medicine and Psychotherapy, Technische Universität München, München, Germany;11. Philadelphia VA Medical Center, Philadelphia, PA, United States;12. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States;13. Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States |
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| Abstract: | BackgroundInflammation-induced pain amplification and hypersensitivity play a role in the pathophysiology of numerous clinical conditions. Experimental endotoxemia has recently been implemented as model to analyze immune-mediated processes in human pain. In this study, we aimed to analyze dose- and time-dependent effects of lipopolysaccharide (LPS) on clinically-relevant pain models for musculoskeletal and neuropathic pain as well as the interaction among LPS-induced changes in inflammatory markers, pain sensitivity and negative affect.MethodsIn this randomized, double-blind, placebo-controlled study, healthy male subjects received an intravenous injection of either a moderate dose of LPS (0.8 ng/kg Escherichia coli), low-dose LPS (0.4 ng/kg), or saline (placebo control group). Pressure pain thresholds (PPT), mechanical pain sensitivity (MPS), and cold pain sensitivity (CP) were assessed before and 1, 3, and 6 h post injection to assess time-dependent LPS effects on pain sensitivity. Plasma cytokines (TNF-α, IL-6, IL-8, IL-10) and state anxiety were repeatedly measured before, and 1, 2, 3, 4, and 6 h after injection of LPS or placebo.ResultsLPS administration induced a systemic immune activation, reflected by significant increases in cytokine levels, body temperature, and negative mood with pronounced effects to the higher LPS dose. Significant decreases of PPTs were observed only 3 h after injection of the moderate dose of LPS (0.8 ng/kg). MPS and CP were not affected by LPS-induced immune activation. Correlation analyses revealed that decreased PPTs were associated with peak IL-6 increases and negative mood.ConclusionsOur results revealed widespread increases in musculoskeletal pain sensitivity in response to a moderate dose of LPS (0.8 ng/kg), which correlate both with changes in IL-6 and negative mood. These data extend and refine existing knowledge about immune mechanisms mediating hyperalgesia with implications for the pathophysiology of chronic pain and neuropsychiatric conditions. |
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| Keywords: | Pain Sickness behavior Endotoxin Lipopolysaccharides Inflammation Cytokines Pressure pain thresholds Mechanical pain sensitivity Anxiety Mood |
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