Connexin‐purinergic signaling in enteric glia mediates the prolonged effect of morphine on constipation

Bhave, Sukhada; Gade, Aravind R; Kang, Minho; Hauser, Kurt F.; Dewey, William L.; Akbarali, Hamid I.

doi:10.1096/fj.201601068r

Cited by 44 publications

(53 citation statements)

References 43 publications

(62 reference statements)

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“…Prolonged treatment with morphine causes a ‘leaky gut’ that predisposes to colonic inflammation. Connexin-purinergic signalling in enteric glia likely mediates the opioid induced constipation (OIC) and inflammation caused by long-term treatment with morphine (Bhave et al, 2017). The mouse model of opioid-induced constipation is associated with colonic inflammation and other features that could be markedly different from OIC in humans.…”

Section: Motility Disordersmentioning

confidence: 99%

Purinergic drug targets for gastrointestinal disorders

Burnstock

Christofi

2017

Current Opinion in Pharmacology

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Purinergic receptors are implicated in the pathogenesis of gastrointestinal disorders and are being explored as potential therapeutic targets. Gut inflammation releases ATP that acts on neuron, glial, epithelial and immune cells. Purinergic signalling in glia and neurons is implicated in enteric neuropathies. Inflammation activates glia to increase ATP release and alter purinergic signalling. ATP release causes neuronal death and gut motor dysfunction in colitis via a P2X7-dependent neural-glial pathway and a glial purinergic-connexin-43 pathway. The latter pathway also mediates morphine-induced constipation and gut inflammation that may differ from opioid-induced constipation (OIC). P2X7R antagonists are protective in inflammatory bowel disease (IBD) models, where as AZD9056 is questionable in CD, but is potentially beneficial for chronic abdominal pain. Drug targets under investigation for IBD, IBS and motility disorders include P2X7R, P2X3R, P2Y2R, A2A/A2BAR, enzymes and transporters.

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Section: Motility Disordersmentioning

confidence: 99%

Purinergic drug targets for gastrointestinal disorders

Burnstock

Christofi

2017

Current Opinion in Pharmacology

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“…On the other hand, in glial cells, P2Y 12 Rs are more highly expressed in Females than Males. Glial cells are important regulators of motility and secretion [24, 25] and may be involved in chronic morphine-induced constipation [26] and visceral pain [27]. P2Y 12 Rs regulate microglial activation and surveillance during neuropathic pain [28].…”

Section: Discussionmentioning

confidence: 99%

Clopidogrel IBS Patients Have Higher Incidence of Gastrointestinal Symptoms Influenced by Age and Gender

et al. 2017

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Background Clopidogrel is an irreversible antagonist of P2Y12 receptors (P2Y12Rs) used as an antiplatelet drug to reduce risk of thrombosis. P2Y12Rs are expressed in gastrointestinal (GI) tract where they might regulate GI function. Aim To evaluate if blockade of P2Y12Rs by clopidogrel is associated with higher incidence of GI symptoms in patients with irritable bowel syndrome (IBS). Methods A retrospective analysis of our institutional database was conducted for a 13-year period. IBS patients were identified, and their demographics, GI symptoms and clopidogrel therapy were collected. Logistic regression models were used to characterize symptoms in clopidogrel versus no-clopidogrel IBS-groups, adjusting for Age and Sex differences. An additional study characterized the P2Y12R distribution in human gut. Results The search identified 7217 IBS patients (6761 no-clopidogrel/456 clopidogrel). There were a higher proportion of patients with GI symptoms on clopidogrel (68%) compared to controls (60%, p = 0.0011) that were Females (70 vs. 60%, p = 0.0003) not Males (61 vs. 60%; p = 0.8312). In Females, clopidogrel was associated with higher incidence of GI symptoms (Age adjusted; p < 0.0001) for pain, constipation, gastroparesis (p ≤ 0.0001) and psychogenic pain (p = 0.0006). Age or Sex (adjusted models) influenced one or more GI symptoms (i.e., pain, p < 0.0001; constipation, p < 0.0001/p = 0.008; diarrhea, flatulence, p = 0.01). P2Y12R immunoreactivity was abundant in human ENS; glial-to-neuron ratio of P2Y12Rs expressed in Females ≫ Males. Conclusions Irreversible blockade of P2Y12R by clopidogrel is associated with higher incidence of GI symptoms in Female IBS patients, although Age or Sex alone contributes to symptomatology. Prospective studies can determine clinical implications of P2Y12Rs in IBS.

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“…Additionally, carbenoxolone has effects in the periphery. Systemic carbenoxolone blocked morphine‐related colonic inflammation and constipation when administered intraperitoneally (Bhave et al, ).…”

Section: Introductionmentioning

confidence: 99%

Analysis of carbenoxolone by ultra‐high‐performance liquid chromatography tandem mass spectrometry in mouse brain and blood after systemic administration

Poklis

Gonek

Wolf

et al. 2019

Biomedical Chromatography

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Carbenoxolone is a derivative of glycyrrhetinic acid found in the root of Glycyrrhiza glabra, colloquially known as licorice. It has been used as a treatment for peptic and oral ulcers. In recent years, carbenoxolone has been utilized in basic research for its ability to block gap junctional communication. Better understanding the distribution of carbenoxolone after systemic administration can lead to a better understanding of its potential sites of action. Presented is an ultra high‐performance liquid chromatography tandem mass spectrometer (UHPLC–MS/MS) method for the identification and quantification of carbenoxolone in mouse blood and brain tissue. Twenty mice were injected intraperitoneally with 25 mg/kg carbenoxolone and brain tissue and blood were collected for analysis. Blood concentrations (mean ± SD) at 15, 30, 60 and 120 min were determined to be (n = 5) 5394 ± 778, 2636 ± 836, 1564 ± 541 and 846 ± 252 ng/mL, respectively. Brain concentrations (mean ± SD) at 15, 30, 60 and 120 mins were determined to be (n = 5) 171 ± 62, 102 ± 35, 55 ± 10 and 27 ± 9 ng/g, respectively. The analysis of these specimens at the four different time points resulted in blood and brain half‐lives in mice of ~43 and 41 min, respectively. The UHPLC–MS/MS method was determined to be sensitive and robust for quantification of carbenoxolone.

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Connexin‐purinergic signaling in enteric glia mediates the prolonged effect of morphine on constipation

Cited by 44 publications

References 43 publications

Purinergic drug targets for gastrointestinal disorders

Purinergic drug targets for gastrointestinal disorders

Clopidogrel IBS Patients Have Higher Incidence of Gastrointestinal Symptoms Influenced by Age and Gender

Analysis of carbenoxolone by ultra‐high‐performance liquid chromatography tandem mass spectrometry in mouse brain and blood after systemic administration

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