Acute experimental endotoxemia induces visceral hypersensitivity and altered pain evaluation in healthy humans
Abstract
Growing evidence suggests that systemic immune activation plays a role in the pathophysiology of pain in functional bowel disorders. By implementing a randomized crossover study with an injection of endotoxin or saline, we aimed to test the hypothesis that endotoxin-induced systemic inflammation increases visceral pain sensitivity in humans. Eleven healthy men (mean ± standard error of the mean age 26.6 ± 1.1 years) received an intravenous injection of either lipopolysaccharide (LPS; 0.4 ng/kg) or saline on 2 otherwise identical study days. Blood samples were collected 15 min before and 1, 2, 3, 4, and 6h after injection to characterize changes in immune parameters including proinflammatory cytokines. Rectal sensory and pain thresholds and subjective pain ratings were assessed with barostat rectal distensions 2h after injection. LPS administration induced an acute inflammatory response indicated by transient increases in tumor necrosis factor alpha, interleukin 6, and body temperature (all P<.001). The LPS-induced immune activation increased sensitivity to rectal distensions as reflected by significantly decreased visceral sensory and pain thresholds (both P<.05) compared to saline control. Visceral stimuli were rated as more unpleasant (P<.05) and inducing increased urge to defecate (P<.01). Pain thresholds correlated with interleukin 6 at +1h (r=0.60, P<.05) and +3h (r=0.67, P<.05) within the LPS condition. This report is novel in that it demonstrates that a transient systemic immune activation results in decreased visceral sensory and pain thresholds and altered subjective pain ratings. Our results support the relevance of inflammatory processes in the pathophysiology of visceral hyperalgesia and underscore the need for studies to further elucidate immune-to-brain communication pathways in gastrointestinal disorders.
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Visceral pain sensitivity thresholds are reduced and visceral pain is rated as more unpleasant after administration of low-dose LPS.
“In addition, visceral pain sensitivity thresholds are reduced and visceral pain (provoked by rectal distension) is rated as more unpleasant after administration of low-dose LPS.28”
From The Gut Microbiome and the Brain (2014) · cites this paper as [28]
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“Building on our transdisciplinary work at the interface of immunopsychiatry, fear learning, and the gut-brain axis (Benson et al., 2020; Benson et al., 2019; Engler et al., 2017; Icenhour et al., 2021; Koenen et al., 2021), we performed two complementary, randomized, double-blind,…”
BackgroundMethodResultInfluentialSelf-citationPain without presence: a narrative review of the pathophysiological landscape of phantom limb pain
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Effects of COX inhibition and LPS on formalin induced pain in the infant rat
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“…immune system (Voituron et al., 2012) and enhances pain in human and nonhuman models through cytokine activation (Watkins et al., 1994; Yirmiya et al., 1994; Cunha et al., 2000; Reeve et al., 2000; Cahill et al., 2003; Bressan et al., 2006; Cao et al., 2009; Benson et al., 2012; Yoon et al., 2012).”
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“It cannot be excluded that the observed changes are connected with other direct influences on the nervous system, including the blockade of synaptic transmissions and/or the influence on sensory stimuli conduction [64, 65].”
BackgroundThe Influence of Pain and Analgesia in Rodent Models of Sepsis
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“Previous investigations have reported that LPS may also impair synaptic transmission and change sensory stimuli conduction (Benson et al. 2012; Meneses et al. 2016).”
BackgroundNociplastic pain mechanisms and toll-like receptors as promising targets for its management
Rodríguez-Palma, E. J., de la Cruz, S. H., Islas-Espinoza, A. M., Castañeda‐Corral, G., Granados‐Soto, V., & Khanna, R. (2024) · Pain · doi:10.1097/j.pain.0000000000003238 · Cited by 14 · see citing works
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“8 pg/ml for TNF-α) (Benson et al., 2012; Wegner et al., 2014), and plasma cortisol was analyzed with commercial ELISA (Cortisol ELISA; IBL International, Hamburg, Germany; detection limit 0.”
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“Previous studies (Benson et al. 2012;Wegner et al. 2014; Janum et al. 2016) have shown a dose-dependent © 2021 The Authors.”
ResultAcute experimental inflammation in healthy women attenuates empathy for psychological pain
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“Pain, a notable stressor, generates inflammatory responses, (Griffis et al., 2013; Zhou et al., 1993) and amplified pain sensitivity serves as an additional inflammatory source that, in turn, provokes depressive symptoms (Benson et al., 2012; Watkins and Maier, 2005).”
BackgroundSo Many Faces, Phases, and Facets, Sickness Behavior Beyond Disciplines
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How Can Experimental Endotoxemia Contribute to Our Understanding of Pain? A Narrative Review
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“In a series of studies [62, 64, 67], low-dose LPS (i.e., 0.4 ng/kg) was implemented to test effects on rectal sensory and pain thresholds.”
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“LPS administration has been shown to affect rectal pain perception whereby both painful stimuli become more painful and the sensitivity to non-painful stimuli is increased (Benson et al., 2012).”
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- Authors
- Benson, S., Kattoor, J., Wegner, A., Hammes, F., Reidick, D., Grigoleit, J.-S., Engler, H., Oberbeck, R., Schedlowski, M., & Elsenbruch, S.
- Affiliations
- Essen University Hospital (DE)
- Corresponding author
- Elsenbruch, Sigrid
- Venue
- Pain
- Published
- 2012-04
- Volume
- 153
- Issue
- 4
- Pages
- 794-799
- ISSN
- 0304-3959 (ISSN-L)
- OpenAlex
- W1975033451
- Cited by
- 89
- References
- 53
- Citations by year
- 2025: 3 · 2024: 4 · 2023: 5 · 2022: 8 · 2021: 6 · 2020: 6 · 2019: 6 · 2018: 4 · 2017: 6 · 2016: 4 · 2015: 13 · 2014: 12 · 2013: 8 · 2012: 4
- FWCI
- 11.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pain (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Keywords
- endotoxemia, lipopolysaccharide, visceral hypersensitivity, visceral pain, systemic inflammation, immune activation, interleukin-6, TNF-α, rectal distension, pain threshold, subjective pain ratings, functional bowel disorders
- MeSH terms
- Adult, Escherichia coli, Escherichia coli Infections, Humans, Lipopolysaccharides, Male, Pain Measurement, Cytokines, Pain Threshold, Cross-Over Studies, Endotoxemia, Young Adult, Visceral Pain, Acute Pain
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