Abdominal pain is common in the general population and, in patients with irritable bowel syndrome, is attributed to visceral hypersensitivity. We found that oral administration of specific Lactobacillus strains induced the expression of mu-opioid and cannabinoid receptors in intestinal epithelial cells, and mediated analgesic functions in the gut-similar to the effects of morphine. These results suggest that the microbiology of the intestinal tract influences our visceral perception, and suggest new approaches for the treatment of abdominal pain and irritable bowel syndrome.
SUMMARY BackgroundThe role of the gut microbiota in patho-physiology of irritable bowel syndrome (IBS) is suggested by several studies. However, standard cultural and molecular methods used to date have not revealed specific and consistent IBS-related groups of microbes.
This uncommissioned review article was subject to full peer-review.
SUMMARY BackgroundIrritable bowel syndrome (IBS), one of the most common gastrointestinal disorders, markedly impairing patients' quality of life. Drug development for IBS treatment has been hampered by the lack of understanding of IBS aetiology. In recent years, numerous data have emerged that suggest the involvement of immune activation in IBS, at least in a subset of patients.
AimTo determine whether immune activation and intestinal permeabilisation are more frequently observed in IBS patients compared with healthy controls.
MethodsThe scientific bibliography was searched using the following keywords: irritable bowel syndrome, inflammation, immune activation, permeabilisation, intestine, assay, histology and human. The retrieved studies, including blood, faecal and histological studies, were analysed to provide a comprehensive and structured overview of the available data including the type of assay, type of inflammatory marker investigated or intestinal segment studied.
ResultsImmune activation was more frequently observed in IBS patients than in healthy controls. An increase in the number of mast cells and lymphocytes, an alteration in cytokine levels and intestinal permeabilisation were reported in IBS patients. No consistent changes in the numbers of B cells or enterochromaffin cells or in mucosal serotonin production were demonstrated.
ConclusionsThe changes observed were modest and often heterogeneous among the studied population. Only appropriate interventions improving irritable bowel syndrome symptoms could highlight and confirm the role of immune activation in this pathophysiology.
The symptoms of irritable bowel syndrome (IBS) include significant abdominal pain and bloating. Current treatments are empirical and often poorly efficacious, and there is a need for the development of new and efficient analgesics aimed at IBS patients. T-type calcium channels have previously been validated as a potential target to treat certain neuropathic pain pathologies. Here we report that T-type calcium channels encoded by the Ca V 3.2 isoform are expressed in colonic nociceptive primary afferent neurons and that they contribute to the exaggerated pain perception in a butyratemediated rodent model of IBS. Both the selective genetic inhibition of Ca V 3.2 channels and pharmacological blockade with calcium channel antagonists attenuates IBS-like painful symptoms. Mechanistically, butyrate acts to promote the increased insertion of Ca V 3.2 channels into primary sensory neuron membranes, likely via a posttranslational effect. The butyrate-mediated regulation can be recapitulated with recombinant Ca V 3.2 channels expressed in HEK cells and may provide a convenient in vitro screening system for the identification of T-type channel blockers relevant to visceral pain. These results implicate T-type calcium channels in the pathophysiology of chronic visceral pain and suggest Ca V 3.2 as a promising target for the development of efficient analgesics for the visceral discomfort and pain associated with IBS.analgesia | visceral nociceptor | sensitization | trafficking I rritable bowel syndrome (IBS) is one of the most prevalent lower gastrointestinal (GI) tract disorders, affecting ∼20% of the population in developed countries. Despite high prevalence and considerable impairment of quality of life, current treatments for IBS are empirical and often poorly effective, and the disorder remains a challenge to clinicians (1). IBS is characterized by abdominal pain and discomfort associated with abnormal bowel functions. Although different etiologies have been proposed, it is generally accepted that IBS is multifactorial and that there are likely multiple molecular targets relevant to innovative drug development strategies (2). Among these, there is considerable interest in dysregulation of the brain-gut pain neuraxis and specific subtypes of ion channels in primary afferent neurons that mediate the detection of nociceptive stimuli and transmission to the CNS (3). Moreover, in a number of animal models of chronic pain, the pathological remodeling of ion channel expression patterns has been linked to the hyperexcitability of primary afferent nociceptors (4, 5).A number of ionic conductances contribute to neuronal firing, including voltage-gated calcium channels, which uniquely both shape action potentials and influence neuronal excitability. In mammals, 10 pore-forming calcium channel α 1 subunit genes have been identified, three of which, Ca V 3.1, Ca V 3.2, and Ca V 3.3, form low-voltage-activated (LVA) T-type calcium channels that are activated by weak depolarizations and generally act to control excitability (6, 7). Al...
In 2004-2017, prescription opioid use in France at least doubled and oxycodone use increased particularly, associated with a nontrivial increase in opioid-related morbidity-mortality. Although giving no indication for an 'opioid epidemic,' these findings call for proper monitoring of opioid use.
T-type calcium channels encoded by the Ca(V)3.2 isoform are expressed in nociceptive primary afferent neurons where they contribute to hyperalgesia and thus are considered as a potential therapeutic target to treat pathological pain. Here we report that the small organic state-dependent T-type channel antagonist TTA-A2 efficiently inhibits recombinant and native Ca(V)3.2 currents. Although TTA-A2 is a pan Ca(V)3 blocker, it demonstrates a higher potency for Ca(V)3.2 compared to Ca(V)3.1. TTA-A2 selectivity for T-type currents was demonstrated in sensory neurons where it lowered cell excitability uniquely on neurons expressing T-type channels. In vivo pharmacology in Ca(V)3.2 knockout and wild type mice reveal that TTA-A2-mediated antinociception critically depends on Ca(V)3.2 expression. The pathophysiology of irritable bowel syndrome (IBS) was recently demonstrated to involve Ca(V)3.2 in a rat model of this disease. Oral administration of TTA-A2 produced a dose-dependent reduction of hypersensitivity in an IBS model, demonstrating its therapeutic potential for the treatment of pathological pain. Overall, our results suggest that the high potency of TTA-A2 in the depolarized state strengthen its analgesic efficacy and selectivity toward pathological pain syndromes. This characteristic would be beneficial for the development of analgesics targeting T-type channels, in particular for the treatment of pain associated with IBS.
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