Brain–Gut Interactions Increase Peripheral Nociceptive Signaling in Mice With Postinfectious Irritable Bowel Syndrome

Ibeakanma, Charles; Ochoa-Cortés, Fernando; Miranda–Morales, Marcela; McDonald, Todd; Spreadbury, Ian; Cenac, Nicolas; Cattaruzza, Fiore; Hurlbut, David; Vanner, S; Bunnett, Nigel W.; Vergnolle, Nathalie; Vanner, Stephen

doi:10.1053/j.gastro.2011.08.006

Cited by 76 publications

(98 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We specifically targeted high-threshold nociceptive afferents in the splanchnic (thoracolumbar) pathway as we have shown that they normally respond to noxious levels of colonic distention/contraction 45,46 . These afferents are known to become hypersensitive 46,47 and hyper-excitable 57,58 in models of chronic visceral pain, which translates to increased signaling of noxious colorectal distention (CRD) within the thoracolumbar spinal cord 59 and enhanced behavioural responses to CRD 48,49 . We have also shown that specific functional deficits in these afferents translate to reduced sensory responses to noxious CRD in whole-animal studies 45 .…”

Section: Resultsmentioning

confidence: 99%

Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain

et al. 2014

View full text Add to dashboard Cite

Poor oral availability and susceptibility to reduction and protease degradation is a major hurdle in peptide drug development. However, drugable receptors in the gut present an attractive niche for peptide therapeutics. Here we demonstrate, in a mouse model of chronic abdominal pain, that oxytocin receptors are significantly upregulated in nociceptors innervating the colon. Correspondingly, we develop chemical strategies to engineer non-reducible and therefore more stable oxytocin analogues. Chemoselective selenide macrocyclization yields stabilized analogues equipotent to native oxytocin. Ultra-high-field nuclear magnetic resonance structural analysis of native oxytocin and the seleno-oxytocin derivatives reveals that oxytocin has a pre-organized structure in solution, in marked contrast to earlier X-ray crystallography studies. Finally, we show that these seleno-oxytocin analogues potently inhibit colonic nociceptors both in vitro and in vivo in mice with chronic visceral hypersensitivity. Our findings have potentially important implications for clinical use of oxytocin analogues and disulphide-rich peptides in general.

show abstract

Section: Resultsmentioning

confidence: 99%

Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Both methods (multiunit spike discharge and waveform analysis) of measurement are routinely used to determine changes in the excitability of the mesenteric nerve fibers induced by different treatments (6,25,27,32,45,49). The timing of the multiunit spikes was determined using the peak detection module of Clampfit, and average frequency was calculated from spike intervals.…”

Section: Off-line Data Analysismentioning

confidence: 99%

Psychoactive bacteriaLactobacillus rhamnosus(JB-1) elicits rapid frequency facilitation in vagal afferents

Perez-Burgos

Wang

Mao

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

205

185

View full text Add to dashboard Cite

Mounting evidence supports the influence of the gut microbiome on the local enteric nervous system and its effects on brain chemistry and relevant behavior. Vagal afferents are involved in some of these effects. We previously showed that ingestion of the probiotic bacterium Lactobacillus rhamnosus (JB-1) caused extensive neurochemical changes in the brain and behavior that were abrogated by prior vagotomy. Because information can be transmitted to the brain via primary afferents encoded as neuronal spike trains, our goal was to record those induced by JB-1 in vagal afferents in the mesenteric nerve bundle and thus determine the nature of the signals sent to the brain. Male Swiss Webster mice jejunal segments were cannulated ex vivo, and serosal and luminal compartments were perfused separately. Bacteria were added intraluminally. We found no evidence for translocation of labeled bacteria across the epithelium during the experiment. We recorded extracellular multi- and single-unit neuronal activity with glass suction pipettes. Within minutes of application, JB-1 increased the constitutive single- and multiunit firing rate of the mesenteric nerve bundle, but Lactobacillus salivarius (a negative control) or media alone were ineffective. JB-1 significantly augmented multiunit discharge responses to an intraluminal distension pressure of 31 hPa. Prior subdiaphragmatic vagotomy abolished all of the JB-1-evoked effects. This detailed exploration of the neuronal spike firing that encodes behavioral signaling to the brain may be useful to identify effective psychoactive bacteria and thereby offer an alternative new perspective in the field of psychiatry and comorbid conditions.

show abstract

“…Serine proteases of bacteria such as the gingipains-R, can also activate PARs [56]. Likewise, an increase of proteolytic activity has been described from samples of post-infectious IBS patients or mouse models [36,38,57]. Even though, the source of these serine-proteases, whether the host epithelial cells or pathogens, needs to be characterized.…”

Section: Endogenous Proteases and Pain Related To Protease-activated mentioning

confidence: 99%

Protease-Activated Receptors as Therapeutic Targets in Visceral Pain

Cenac

2013

Self Cite

View full text Add to dashboard Cite

Abstract:The protease-activated receptors (PARs) play a pivotal role in inflammatory and nociceptive processes. PARs have raised considerable interest because of their capacity to regulate numerous aspects of viscera physiology and pathophysiology. The present article summarizes research on PARs and proteases as signalling molecules in visceral pain. In particular, experiments in animal models suggest that PAR 2 is important for visceral hypersensitivity. Moreover, endogenous PAR 2 agonists seem to be released by colonic tissue of patients suffering from irritable bowel syndrome, suggesting a role for this receptor in visceral pain perception. Thus, PARs, together with proteases that activate them, represent exciting targets for therapeutic intervention on visceral pain.

show abstract

Brain–Gut Interactions Increase Peripheral Nociceptive Signaling in Mice With Postinfectious Irritable Bowel Syndrome

Cited by 76 publications

References 31 publications

Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain

Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain

Psychoactive bacteriaLactobacillus rhamnosus(JB-1) elicits rapid frequency facilitation in vagal afferents

Protease-Activated Receptors as Therapeutic Targets in Visceral Pain

Contact Info

Product

Resources

About