title: Why sickness hurts: A central mechanism for pain induced by peripheral inflammation.
abstract: Low-grade systemic inflammation has been implicated in chronic pain, as well as in comorbid diseases like depression and fatigue. We have previously shown that women's pain perception and regulation is more affected by systemic inflammation than that of men. Here we investigated the neural substrates underlying these effects using an fMRI paradigm previously employed in a clinical population. Fifty-one participants (29 women) were injected with 0.6ng/kg lipopolysaccharide (LPS) or saline to induce a peripheral inflammatory response. The subjects were then tested with a pressure pain fMRI paradigm designed to capture descending pain inhibitory activity 2h after injection, and blood was sampled for cytokine analysis. The subjects injected with LPS became more pain sensitive compared to the placebo group, and the heightened pain sensitivity was paralleled by decreased activity in the ventrolateral prefrontal cortex and the rostral anterior cingulate cortex (rACC) compared to placebo; areas involved in descending pain regulation. The LPS group also had higher activity in the anterior insular cortex, an area underpinning affective and interoceptive pain processing. Women displayed overall less pain-evoked rACC activity compared to men, which may have rendered women less resilient to immune provocation, possibly explaining sex differences in LPS-induced pain sensitivity. Our findings elucidate the pain-related brain circuits affected by experimental peripheral inflammation, strengthening the theoretical link between systemic inflammation and weakened pain regulation in chronic pain disorders. The results further suggest a possible mechanism underlying the female predominance in many chronic pain disorders.
authors.affiliation: Karolinska Pain Center, Behavioral Medicine Pain Treatment Service, Karolinska University Hospital, Solna, Sweden; Stress Research Institute, Stockholm University, Stockholm, Sweden; Department of Clinical Neuroscience, 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 and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: K B
authors.initials: KB
authors.lastname: Jensen
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Osher Center for Integrative Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Kosek
authors.affiliation: Aging Research Center (ARC), Department of Neurobiology, Cares Sciences and Society, Karolinska Institutet and Stockholm University, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Kalpouzos
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 and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Ingvar
authors.affiliation: Osher Center for Integrative Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Department of Medicine Solna and CMM, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Olgart Höglund
authors.affiliation: Stress Research Institute, Stockholm University, Stockholm, Sweden; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Osher Center for Integrative Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Lekander
authors.affiliation: Stress Research Institute, Stockholm University, Stockholm, Sweden; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Osher Center for Integrative Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Axelsson
mesh_terms: D000293:Adolescent; D000328:Adult; D016207:Cytokines / Q000097:blood*; D005260:Female; D006179:Gyrus Cinguli / Q000000981:diagnostic imaging / Q000503:physiopathology*; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000139:chemically induced; D065812:Interoception / Q000502:physiology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000000981:diagnostic imaging / Q000209:etiology / Q000503:physiopathology*; D058748:Pain Perception / Q000502:physiology*; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000503:physiopathology*; D011897:Random Allocation; D012737:Sex Factors; D055815:Young Adult
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides
keywords: Anterior cingulate cortex; Chronic pain; Cytokines; Descending pain inhibition; Insula; Lipopolysaccharide; Pre-frontal cortex; Sickness behavior; fMRI