title: Inflammation-induced pain sensitization in men and women: does sex matter in experimental endotoxemia?
abstract: A role of the innate immune system is increasingly recognized as a mechanism contributing to pain sensitization. Experimental administration of the bacterial endotoxin lipopolysaccharide (LPS) constitutes a model to study inflammation-induced pain sensitization, but all existing human evidence comes from male participants. We assessed visceral and musculoskeletal pain sensitivity after low-dose LPS administration in healthy men and women to test the hypothesis that women show greater LPS-induced hyperalgesia compared with men. In this randomized, double-blind, placebo-controlled crossover study, healthy men (n = 20) and healthy women using oral contraceptives (n = 20) received an intravenous injection of 0.4 ng/kg body weight LPS or placebo. Pain sensitivity was assessed with established visceral and musculoskeletal pain models (ie, rectal pain thresholds; pressure pain thresholds for different muscle groups), together with a heartbeat perception (interoceptive accuracy) task. Plasma cytokines (tumor necrosis factor-α and interleukin-6) were measured along with state anxiety at baseline and up to 6-hour postinjection. Lipopolysaccharide application led to significant increases in plasma cytokines and state anxiety and decreased interoceptive awareness in men and women (P < 0.001, condition effects), with more pronounced LPS-induced cytokine increases in women (P < 0.05, interaction effects). Although both rectal and pressure pain thresholds were significantly decreased in the LPS condition (all P < 0.05, condition effect), no sex differences in endotoxin-induced sensitization were observed. In summary, LPS-induced systemic immune activation leads to visceral and musculoskeletal hyperalgesia, irrespective of biological sex. These findings support the broad applicability of experimental endotoxin administration as a translational preclinical model of inflammation-induced pain sensitization in both sexes.
authors.affiliation: Clinic for Trauma Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany Institute of Clinical and Interventional Radiology and Neuroradiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Wegner
authors.forename: Sigrid
authors.initials: S
authors.lastname: Elsenbruch
authors.forename: Laura
authors.initials: L
authors.lastname: Rebernik
authors.forename: Till
authors.initials: T
authors.lastname: Roderigo
authors.forename: Elisa
authors.initials: E
authors.lastname: Engelbrecht
authors.forename: Marcus
authors.initials: M
authors.lastname: Jäger
authors.forename: Harald
authors.initials: H
authors.lastname: Engler
authors.forename: Manfred
authors.initials: M
authors.lastname: Schedlowski
authors.forename: Sven
authors.initials: S
authors.lastname: Benson
mesh_terms: D000293:Adolescent; D000328:Adult; D002097:C-Reactive Protein / Q000378:metabolism; D018592:Cross-Over Studies; D016207:Cytokines / Q000097:blood; D004311:Double-Blind Method; D019446:Endotoxemia / Q000139:chemically induced / Q000150:complications*; D005260:Female; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007249:Inflammation / Q000150:complications* / Q000209:etiology*; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000097:blood / Q000145:classification / Q000209:etiology*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D012727:Sex Characteristics; D011795:Surveys and Questionnaires; D013997:Time Factors; D055815:Young Adult
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D002097:C-Reactive Protein; D006854:Hydrocortisone