μ-Opioid Receptor–Mediated Enteric Glial Activation Is Involved in Morphine-Induced Constipation

Gao, Hui; Zhang, Yuxin; Li, Yansong; Chang, Haiqing; Cheng, Bo; Li, Na; Yuan, Wei; Li, Shuang; Wang, Qiang

doi:10.1007/s12035-021-02286-0

Cited by 4 publications

(5 citation statements)

References 37 publications

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“…Importantly, our findings show that synergy or additive effect between the mu-opioid receptors in both the CNS and GI tract is essential for understanding OIC and how to treat it effectively. These findings contradict reports suggesting that OIC occurred through a mechanism involving predominantly the mu-opioid receptors located within the GI tract [17][18][19][20][21][22][23] . We also support our results by designing and evaluating a peripherally restricted opioid agonist (AG10-Oxycodone conjugate) that confirms the predominant role of the CNS in precipitating OIC.…”

contrasting

confidence: 99%

“…[6][7][8] provide insights that highlight the critical role of mu-opioid receptors, in both CNS and peripheral nervous system, in causing OIC. Importantly, our findings on the critical role of the mu-opioid receptors in the CNS for causing OIC challenge the theory that morphine and other opioid agonists reduce GI motility through a mechanism involving predominantly the mu-opioid receptors in the GI tract and that the CNS contribution to constipation is minor [17][18][19][20][21][22][23] . This information provides clues that explain deficiencies associated with current PAMORAs.…”

Section: Development Of a Peripherally Restricted Opioid Agonist Probementioning

confidence: 73%

“…These variations made it difficult to draw conclusions about the exact role of the peripheral nervous system and CNS in mediating analgesia and other side effects of opioid medications. For example, it was suggested that morphine and other opioid agonists reduce GI motility through a mechanism involving predominantly the mu-opioid receptors in the GI tract and that the CNS contribution to constipation is minor [17][18][19][20][21][22][23] . This was based on experiments where OIC was fully reversed by PAMORAs (assumed incorrectly to act only peripherally) that are concomitantly administered with morphine.…”

Section: Discussionmentioning

confidence: 99%

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Peripherally restricted transthyretin-based delivery system for probes and therapeutics avoiding opioid-related side effects

et al. 2022

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Several investigations into the sites of action of opioid analgesics have utilized peripherally acting mu-opioid receptor antagonists (PAMORAs), which have been incorrectly assumed to possess limited permeability across the blood-brain barrier. Unfortunately, the poor pharmacokinetic properties of current PAMORAs have resulted in misunderstandings of the role of central nervous system and gastrointestinal tract in precipitating side effects such as opioid-induced constipation. Here, we develop a drug delivery approach for restricting the passage of small molecules across the blood-brain barrier. This allows us to develop naloxone- and oxycodone-based conjugates that display superior potency, peripheral selectivity, pharmacokinetics, and efficacy in rats compared to other clinically used PAMORAs. These probes allow us to demonstrate that the mu-opioid receptors in the central nervous system have a fundamental role in precipitating opioid-induced constipation. Therefore, our conjugates have immediate use as pharmacological probes and potential therapeutic agents for treating constipation and other opioid-related side effects.

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contrasting

confidence: 99%

Section: Development Of a Peripherally Restricted Opioid Agonist Probementioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

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Peripherally restricted transthyretin-based delivery system for probes and therapeutics avoiding opioid-related side effects

et al. 2022

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“…However, the efficacy of the combination of these drugs is limited, and the recurrence rate is high. The combined use of these drugs is also often associated with significant adverse drug reactions ( Rocchio and Ward, 2021 ) such as drug addiction ( Volkow and McLellan, 2016 ; Gao et al, 2021 ), adverse gastrointestinal reactions, and hypertension ( Le et al, 2021 ). Electroacupuncture (EA) is widely used as an effective analgesic therapy in clinical practice.…”

Section: Introductionmentioning

confidence: 99%

Rostral Anterior Cingulate Cortex–Ventrolateral Periaqueductal Gray Circuit Underlies Electroacupuncture to Alleviate Hyperalgesia but Not Anxiety-Like Behaviors in Mice With Spared Nerve Injury

Zhu

Shen

et al. 2022

Front. Neurosci.

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Neuropathic pain is a common cause of chronic pain and is often accompanied by negative emotions, making it complex and difficult to treat. However, the neural circuit mechanisms underlying these symptoms remain unclear. Herein, we present a novel pathway associated with comorbid chronic pain and anxiety. Using chemogenetic methods, we found that activation of glutamatergic projections from the rostral anterior cingulate cortex (rACCGlu) to the ventrolateral periaqueductal gray (vlPAG) induced both hyperalgesia and anxiety-like behaviors in sham mice. Inhibition of the rACCGlu-vlPAG pathway reduced anxiety-like behaviors and hyperalgesia in the spared nerve injury (SNI) mice model; moreover, electroacupuncture (EA) effectively alleviated these symptoms. Investigation of the related mechanisms revealed that the chemogenetic activation of the rACCGlu-vlPAG circuit effectively blocked the analgesic effect of EA in the SNI mice model but did not affect the chronic pain-induced negative emotions. This study revealed a novel pathway, the rACCGlu-vlPAG pathway, that mediates neuropathic pain and pain-induced anxiety.

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“…Another study showed that enteric glial LPAR1 signaling regulates gastrointestinal motility through EGCs and may contribute to chronic intestinal pseudo-obstruction in humans[ 36 ]. Activation of opioid receptors in EGCs may be associated with morphine-induced constipation[ 37 ]. Previous studies have shown that the key components of JCD are associated with neural apoptosis, and many of them also involve changes in AKT protein.…”

Section: Discussionmentioning

confidence: 99%

Ji-Chuan decoction ameliorates slow transit constipation via regulation of intestinal glial cell apoptosis

Wang¹,

Lv²,

Qin³

et al. 2022

WJG

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BACKGROUND Slow transit constipation (STC) is a common intestinal disease with increasing incidence. STC results from various factors, such as the enteric nervous system and metabolic changes. As a classical formula of traditional Chinese medicine, Ji-Chuan decoction (JCD) has been extensively and effectively used in STC treatment, yet its pharmacological mechanism remains unclear. AIM To explore the integrated regulatory pattern of JCD against STC through hyphenated techniques from metabolism, network pharmacology and molecular methods. METHODS STC model mice were generated by intragastric administration of compound diphenoxylate (10 mg/kg/d) for 14 d. The STC mice in the low dose of JCD (3.04 g/kg), middle dose of JCD (6.08 g/kg) and high dose of JCD (12.16 g/kg) groups were orally administered JCD solution once a day for 2 wk. The acetylcholine (ACH) level was examined by enzyme-linked immunosorbent assay. The pathological features of colon tissue were observed by hematoxylin and eosin staining. The differentially expressed metabolites and metabolic pathways were tested by nontargeted metabolomics. The main targets and core ingredients of JCD were identified by network pharmacology, and the expression of AKT was confirmed by immunohistochemistry. Finally, the pathways involved in JCD treatment were predicted using a combination of differentially expressed metabolites and targets, and intestinal glial cell apoptosis was demonstrated by immunofluorescence. RESULTS JCD significantly promoted intestinal motility, increased the levels of the excitatory neurotransmitter ACH and reduced intestinal inflammation in STC mice. Untargeted metabolomics results showed that JCD significantly restored metabolic dysfunction and significantly affected taurine and hypotaurine metabolism. Network pharmacology and molecular experiments showed that JCD regulates AKT protein expression, and the core component is quercetin. Combined analysis demonstrated that apoptosis may be an important mechanism by which JCD relieves constipation. Further experiments showed that JCD reduced enteric glial cell (EGC) apoptosis. CONCLUSION This work demonstrated that reducing EGC apoptosis may be the critical mechanism by which JCD treats STC. These findings call for further molecular research to facilitate the clinical application of JCD.

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μ-Opioid Receptor–Mediated Enteric Glial Activation Is Involved in Morphine-Induced Constipation

Cited by 4 publications

References 37 publications

Peripherally restricted transthyretin-based delivery system for probes and therapeutics avoiding opioid-related side effects

Peripherally restricted transthyretin-based delivery system for probes and therapeutics avoiding opioid-related side effects

Rostral Anterior Cingulate Cortex–Ventrolateral Periaqueductal Gray Circuit Underlies Electroacupuncture to Alleviate Hyperalgesia but Not Anxiety-Like Behaviors in Mice With Spared Nerve Injury

Ji-Chuan decoction ameliorates slow transit constipation via regulation of intestinal glial cell apoptosis

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