Experimental endotoxemia as a model to study neuroimmune mechanisms in human visceral pain

Abstract

The administration of bacterial endotoxin (i.e., lipopolysaccharide, LPS) constitutes a well‐established experimental approach to study the effects of an acute and transient immune activation on physiological, behavioral, and emotional aspects of sickness behavior in animals and healthy humans. However, little is known about possible effects of experimental endotoxemia on pain in humans. This knowledge gap is particularly striking in the context of visceral pain in functional as well as chronic‐inflammatory gastrointestinal disorders. Although inflammatory processes have been implicated in the pathophysiology of visceral pain, it remains incompletely understood how inflammatory mediators interact with bottom–up (i.e., increased afferent input) and top–down (i.e., altered central pain processing) mechanisms of visceral hyperalgesia. Considering the recent findings of visceral hyperalgesia after LPS application in humans, in this review, we propose that experimental endotoxemia with its complex peripheral and central effects constitutes an experimental model to study neuroimmune communication in human pain research. We summarize and attempt to integrate relevant animal and human studies concerning neuroimmune communication in visceral and somatic pain, discuss putative mechanisms, and conclude with future research directions.

Inflammation-induced pain sensitization in men and women

“… 19 , 42 – 45 , 53 , 61 Experimental administration of the bacterial endotoxin LPS offers a reliable model to study inflammation-induced pain sensitization. 2 , 30 , 55 However, with 1 recent exception, 32 virtually all existing knowledge about LPS-induced pain responses in humans is based on data from male volunteers, underscoring the need for studies comparing men and women. Therefore, in this randomized, double-blind, placebo-controlled crossover study, we assessed visceral and musculoskeletal pain sensitivity after low-dose LPS administration in healthy men and in women on hormonal contraceptives.…”

“…Based on these convergent findings, the potential of experimental endotoxemia as a preclinical model to study inflammation-mediated sensitization in the context of immune-targeted drugs has been proposed. 2 , 30 Importantly, however, with the exception of 1 recent study, 32 all existing pain-related human findings during LPS-induced endotoxemia thus far have come from studies conducted exclusively in male participants. 4 , 13 , 31 , 65 Therefore, our goal in this follow-up study was to compare LPS-induced pain sensitization in men and women.…”

Mental Health Comorbidities in Pediatric Chronic Pain: A Narrative Review of Epidemiology, Models, Neurobiological Mechanisms and Treatment

“…Injury leads to the activation of microglia in the dorsal horn of the spinal cord, which results in the release of cytokines and growth factors that excite nociceptive dorsal horn neurons, contributing to the development of central sensitization and hyperalgesia [120] as well as the pathogenesis of chronic pain [121,122]. It is important to note that chronic inflammatory processes are not specific to pain (e.g., autoimmune diseases, aging) [123,124] and may arise from acute immune challenges [125]. Therefore, other conditions that incite neuro-inflammatory responses may also lead to chronic pain and comorbid conditions.…”

Skin colour changes during experimentally-induced sickness

“…The model of LPS administration is a well-established model to experimentally induce an acute sickness response in humans (Schedlowski et al, 2014;Suffredini et al, 1999). LPS elicits a transient innate immune response characterised by a production of pro-inflammatory cytokines, and accompanied by flu-like symptoms including fever, headaches, nausea and changes in fatigue, concentration and mood (Benson et al, 2012;Schedlowski et al, 2014;Suffredini et al, 1999). We set out to investigate skin colour changes during an acute systemic inflammation using spectrophotometric measures and reported change in terms of skin lightness, redness and yellowness.…”