title: Inflammation-induced hyperalgesia: effects of timing, dosage, and negative affect on somatic pain sensitivity in human experimental endotoxemia.
abstract: BACKGROUND
  Inflammation-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.
  
  
  METHODS
  In 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 Escherichiacoli), 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 6h 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 6h after injection of LPS or placebo.
  
  
  RESULTS
  LPS 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 3h 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Clinic for Trauma Surgery, University Hospital Essen, University of Duisburg-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, Germany.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Elsenbruch
authors.affiliation: Institute of Medical Psychology & Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Maluck
authors.affiliation: Institute of Medical Psychology & Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Germany.
authors.forename: Jan-Sebastian
authors.initials: JS
authors.lastname: Grigoleit
authors.affiliation: Institute of Medical Psychology & Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Engler
authors.affiliation: Clinic for Trauma Surgery, University Hospital Essen, University of Duisburg-Essen, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Jäger
authors.affiliation: Paul Ehrlich Institute, Federal Agency for Sera and Vaccines, Langen, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Spreitzer
authors.affiliation: Institute of Medical Psychology & Behavioral Immunobiology, University Hospital Essen, University of Duisburg-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, Germany. Electronic address: sven.benson@uk-essen.de.
authors.forename: Sven
authors.initials: S
authors.lastname: Benson
mesh_terms: D000328:Adult; D000339:Affect / Q000187:drug effects*; D001007:Anxiety / Q000209:etiology / Q000503:physiopathology; D003080:Cold Temperature / Q000009:adverse effects; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D019446:Endotoxemia / Q000150:complications* / Q000503:physiopathology / Q000523:psychology; D005334:Fever / Q000209:etiology; D064368:Healthy Volunteers; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D006930:Hyperalgesia / Q000209:etiology* / Q000503:physiopathology; D007275:Injections, Intravenous; D015850:Interleukin-6 / Q000097:blood / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D059352:Musculoskeletal Pain / Q000209:etiology* / Q000503:physiopathology; D010147:Pain Measurement; D058748:Pain Perception / Q000502:physiology*; D017288:Pain Threshold / Q000187:drug effects*; D011312:Pressure / Q000009:adverse effects; D055815:Young Adult
chemical_list: D016207:Cytokines; C508600:IL6 protein, human; D015850:Interleukin-6; D008070:Lipopolysaccharides; D006854:Hydrocortisone
keywords: Anxiety; Cytokines; Endotoxin; Inflammation; Lipopolysaccharides; Mechanical pain sensitivity; Mood; Pain; Pressure pain thresholds; Sickness behavior