Post-inflammatory colonic afferent sensitisation: different subtypes, different pathways and different time courses

Hughes, Patrick A.; Brierley, Stuart M.; Martin, Christopher M.; Brookes, Simon Jonathan; Linden, David R.; Blackshaw, L. Ashley

doi:10.1136/gut.2008.170811

Cited by 163 publications

(246 citation statements)

References 39 publications

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“…Experiments were restricted to male mice to control for the potential effects of sex steroids on pain responses (Miranda et al, 2011;Myers et al, 2011). Colitis was induced the next morning by a single intrarectal administration of 0.1 ml trinitrobenzene sulfonic acid (TNBS) (Sigma) (130 µg/ml / 30% ethanol) via a polyethylene catheter inserted 3 cm from the anus of isoflurane-anaesthetised mice as previously described (Brierley et al, 2009;Harrington et al, 2012;Hughes et al, 2009b). After 28 days mice were used for experiments.…”

Section: Chronic Visceral Hypersensitivity Model (Cvh Mice)mentioning

confidence: 99%

“…Distension of the colo-rectum is sensed by mechanosensitive extrinsic primary sensory afferent nerves, which are best characterized in the mouse (Brierley et al, 2004;Hughes et al, 2009b). Muscular / mucosal afferents respond to fine tactile stimuli and low intensity circular stretch, and in the colo-rectum are unique to the pelvic afferent pathway where they comprise approximately 25% of the total afferent population (Brierley et al, 2004;Feng et al, 2010;Hughes et al, 2009b).…”

Section: Introductionmentioning

confidence: 99%

“…Muscular / mucosal afferents respond to fine tactile stimuli and low intensity circular stretch, and in the colo-rectum are unique to the pelvic afferent pathway where they comprise approximately 25% of the total afferent population (Brierley et al, 2004;Feng et al, 2010;Hughes et al, 2009b). These afferent nerves respond linearly to increasing levels of distension and signal into the noxious range.…”

Section: Introductionmentioning

confidence: 99%

“…This colitis is transient, peaking several days after administration and then spontaneously healing such that by 28 days following administration the histology of the colon and myeloperoxidase levels do not differ from untreated animals (Hughes et al, 2009a;Hughes et al, 2009b;Krauter et al, 2007;Qin et al, 2011). However, colonic afferent nerves remain sensitized to distension long after the mucosa heals, which models aspects of the chronic visceral hypersensitivity (CVH) experienced by IBS patients (Gschossmann et al, 2004;Hughes et al, 2009a;Hughes et al, 2009b). In this model muscular / mucosal afferents are sensitized to mucosal stroking but not circular stretch, and the sensitization observed is relatively modest compared to hypersensitivity displayed by high-threshold afferents (Hughes et al, 2009b).…”

Section: Introductionmentioning

confidence: 99%

“…However, colonic afferent nerves remain sensitized to distension long after the mucosa heals, which models aspects of the chronic visceral hypersensitivity (CVH) experienced by IBS patients (Gschossmann et al, 2004;Hughes et al, 2009a;Hughes et al, 2009b). In this model muscular / mucosal afferents are sensitized to mucosal stroking but not circular stretch, and the sensitization observed is relatively modest compared to hypersensitivity displayed by high-threshold afferents (Hughes et al, 2009b). The molecular changes underlying the sensitization of colo-rectal sensory afferents following recovery from inflammation and the contribution by opioid receptors to CVH in this model remain to be determined.…”

Section: Introductionmentioning

confidence: 99%

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Immune derived opioidergic inhibition of viscerosensory afferents is decreased in Irritable Bowel Syndrome patients

Hughes

Moretta

Lim

et al. 2014

Brain, Behavior, and Immunity

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Immune derived opioidergic inhibition of viscerosensory afferents is decreased in Irritable Bowel Syndrome patients, Brain, Behavior, and Immunity (2014), doi: http://dx.doi.org/10. 1016/j.bbi.2014.07.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. supernatants from HS and IBS patients were applied to colo-rectal sensory afferent endings in mice with post-inflammatory chronic visceral hypersensitivity (CVH). β-endorphin was identified predominantly in monocyte / macrophages relative to T or B cells in human PBMC and colonic lamina propria. Monocyte derived β-endorphin levels and colonic macrophage numbers were lower in IBS patients than healthy subjects. PBMC supernatants from healthy subjects had greater inhibitory effects on colo-rectal afferent mechanosensitivity than those from IBS patients. The inhibitory effects of PBMC supernatants were more prominent in CVH mice compared to healthy mice due to an increase in µ-opioid receptor expression in dorsal root ganglia neurons in CVH mice. Monocyte / macrophages are the predominant immune cell type responsible for β-endorphin secretion in humans. IBS patients have lower monocyte derived β-endorphin levels than healthy subjects, causing less inhibition of colonic afferent endings. Consequently, altered immune function contributes toward visceral hypersensitivity in IBS.

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Section: Chronic Visceral Hypersensitivity Model (Cvh Mice)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Immune derived opioidergic inhibition of viscerosensory afferents is decreased in Irritable Bowel Syndrome patients

Hughes

Moretta

Lim

et al. 2014

Brain, Behavior, and Immunity

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Oxytocin Verbindungen zur oralen Behandlung von Bauchschmerzen

Kremsmayr,

Schober,

Kaltenböck

et al. 2024

Angewandte Chemie

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Abdominal pain presents an onerous reality for millions of people affected by gastrointestinal disorders such as irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD). The oxytocin receptor (OTR) has emerged as a new analgesic drug target with OTR expression upregulated on colon‐innervating nociceptors in chronic visceral hypersensitivity states, accessible via luminal delivery. However, the low gastrointestinal stability of OTR’s endogenous peptide ligand oxytocin (OT) is a bottleneck for therapeutic development. Here, we report the development of potent and fully gut‐stable OT analogues, laying the foundation for a new area of oral gut‐specific peptide therapeutics. Ligand optimisation guided by structure‐gut‐stability‐activity relationships yielded highly stable analogues (t1/2 >24 h, compared to t1/2 <10 min of OT in intestinal fluid) equipotent to OT (~3 nM) and with enhanced OTR selectivity. Intra‐colonic administration of the lead ligand significantly reduced colonic mechanical hypersensitivity in a concentration‐dependent manner in a mouse model of chronic abdominal pain. Moreover, oral administration of the lead ligand also displayed significant analgesia in this abdominal pain mouse model. The generated ligands and employed strategies could pave the way to a new class of oral gut‐specific peptides to study and combat chronic gastrointestinal disorders, an area with substantial unmet medical needs.

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