title: Modality and sex differences in pain sensitivity during human endotoxemia.
abstract: Systemic inflammation can induce pain hypersensitivity in animal and human experimental models, and has been proposed to be central in clinical pain conditions. Women are overrepresented in many chronic pain conditions, but experimental studies on sex differences in pain regulation during systemic inflammation are still scarce. In two randomized and double blind placebo controlled experiments, we used low doses of lipopolysaccharide (LPS) as an experimental model of systemic inflammation. The first study employed 0.8ng/kg LPS in a within-subject design of 8 individuals (1 woman), and the second study 0.6ng/kg LPS in a between-subject design of 52 participants (29 women). We investigated the effect on (a) pressure, heat, and cold pain thresholds, (b) suprathreshold noxious heat and cold sensitivity, and (c) conditioned pain modulation (CPM), and differences between men and women. LPS induced significantly lower pressure pain thresholds as compared to placebo (mean change with the 0.8ng/kg dose being -64±30kPa P=.04; with the 0.6ng/kg dose -58±55kPa, P<.01, compared to before injection), whereas heat and cold pain thresholds remained unaffected (P's>.70). Suprathreshold noxious pain was not affected by LPS in men (P's⩾.15). However, LPS made women rated suprathreshold noxious heat stimuli as more painful (P=.01), and showed a tendency to rate noxious cold pain as more painful (P=.06) as compared to placebo. Furthermore, LPS impaired conditioned pain modulation, a measure of endogenous pain inhibition, but this effect was also restricted to women (P<.01, for men P=.27). Pain sensitivity correlated positively with plasma IL-6 and IL-8 levels. The results show that inflammation more strongly affects deep pain, rather than cutaneous pain, and suggest that women's pain perception and modulation is more sensitive to immune activation than men's.
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Osher Center for Integrative Medicine, Karolinska Institutet, Stockholm, Sweden. Electronic address: bianka.karshikoff@ki.se.
authors.forename: B
authors.initials: B
authors.lastname: Karshikoff
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Osher Center for Integrative Medicine, Karolinska Institutet, Stockholm, Sweden; Stress Research Institute, Stockholm University, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Lekander
authors.affiliation: Department of Anesthesiology and Intensive Care, Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Soop
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Osher Center for Integrative Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: F
authors.initials: F
authors.lastname: Lindstedt
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Osher Center for Integrative Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Ingvar
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Osher Center for Integrative Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Kosek
authors.affiliation: Stress Research Institute, Stockholm University, Stockholm, Sweden; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Olgart Höglund
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Osher Center for Integrative Medicine, Karolinska Institutet, Stockholm, Sweden; Stress Research Institute, Stockholm University, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Axelsson
mesh_terms: D000328:Adult; D003080:Cold Temperature; D004311:Double-Blind Method; D019446:Endotoxemia / Q000097:blood / Q000503:physiopathology*; D005260:Female; D006358:Hot Temperature; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000503:physiopathology*; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D008297:Male; D010146:Pain / Q000097:blood / Q000503:physiopathology*; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology*; D011312:Pressure; D012727:Sex Characteristics; D055815:Young Adult
chemical_list: D015850:Interleukin-6; D016209:Interleukin-8
keywords: Cold pressor; Conditioned pain modulation; Cytokines; Endotoxin; Inflammation; Lipopolysaccharide; Pain; Pressure point thresholds; Sickness behavior