Opioid Use in Murine Model Results in Severe Gastric Pathology that May Be Attenuated by Proton Pump Inhibition

Ghosh, Nillu; Kesh, Kousik; Ramakrishnan, Sundaram; Roy, Sabita

doi:10.1016/j.ajpath.2022.04.005

Cited by 10 publications

(6 citation statements)

References 53 publications

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“…Additionally, preclinical studies in adults have shown that opioid-induced gut dysbiosis has adverse consequences on gut histology, including epithelial cell injury as well as apical villous expulsion and inflammatory cell influx into the lumen. 38 , 39 , 59 , 60 As MET mice had significantly altered fecal microbiota, we next investigated whether alterations to the gut microbiota conferred changes to colonic histology, using established histological criteria based on epithelial damage, inflammation, and epithelial expulsion to lumen, previously described 39 ( Figure 6c, d ). Modest changes were observed in H&E-stained colonic sections from MET and CTRL offspring ( Figure 6c ).…”

Section: Resultsmentioning

confidence: 99%

Opioid-induced dysbiosis of maternal gut microbiota during gestation alters offspring gut microbiota and pain sensitivity

Abu,

Singh,

Tao

et al. 2023

Gut Microbes

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There has been a rapid increase in neonates born with a history of prenatal opioid exposure. How prenatal opioid exposure affects pain sensitivity in offspring is of interest, as this may perpetuate the opioid epidemic. While few studies have reported hypersensitivity to thermal pain, potential mechanisms have not been described. This study posits that alterations in the gut microbiome may underly hypersensitivity to pain in prenatally methadone-exposed 3-week-old male offspring, which were generated using a mouse model of prenatal methadone exposure. Fecal samples collected from dams and their offspring were subjected to 16s rRNA sequencing. Thermal and mechanical pain were assessed using the tail flick and Von Frey assays. Transcriptomic changes in whole brain samples of opioid or saline-exposed offspring were investigated using RNA-sequencing, and midbrain sections from these animals were subjected to qPCR profiling of genes related to neuropathic and inflammatory pain pathways. Prenatal methadone exposure increased sensitivity to thermal and mechanical pain and elevated serum levels of IL-17a. Taxonomical analysis revealed that prenatal methadone exposure resulted in significant alterations in fecal gut microbiota composition, including depletion of Lactobacillus , Bifidobacterium , and Lachnospiracea sp and increased relative abundance of Akkermansia, Clostridium sensu stricto 1 , and Lachnoclostridium . Supplementation of the probiotic VSL#3 in dams rescued hypersensitivity to thermal and mechanical pain in prenatally methadone-exposed offspring. Similarly, cross-fostering prenatally methadone-exposed offspring to control dams also attenuated hypersensitivity to thermal pain in opioid-exposed offspring. Modulation of the maternal and neonatal gut microbiome with probiotics resulted in transcriptional changes in genes related to neuropathic and immune-related signaling in whole brain and midbrain samples of prenatally methadone-exposed offspring. Together, our work provides compelling evidence of the gut-brain-axis in mediating pain sensitivity in prenatally opioid-exposed offspring.

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Section: Resultsmentioning

confidence: 99%

Opioid-induced dysbiosis of maternal gut microbiota during gestation alters offspring gut microbiota and pain sensitivity

Abu,

Singh,

Tao

et al. 2023

Gut Microbes

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“…In particular, metabolic changes in morphine-tolerant mice were mitigated, raising the question of whether changes in the plasma metabolites following acute morphine intake were contributing to morphine analgesic effects and whether they could serve as tolerance indicators. The role of metabolic changes in morphine-mediated pathologies [ 43 , 51 , 52 , 53 , 54 , 55 ] demands additional studies. Our findings warrant further investigation in other morphine tolerance models and humans.…”

Section: Discussionmentioning

confidence: 99%

Changes in Plasma Metabolic Signature upon Acute and Chronic Morphine Administration in Morphine-Tolerant Mice

Kutchy

Palermo

et al. 2023

Metabolites

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Morphine administration causes system-level metabolic changes. Here, we show that morphine-tolerant mice exhibited distinct plasma metabolic signatures upon acute and chronic administration. We utilized a mouse model of morphine tolerance by exposing mice to increasing doses of the drug over 4 days. We collected plasma samples from mice undergoing acute or chronic morphine or saline injections and analyzed them using targeted GC–MS-based metabolomics to profile approximately 80 metabolites involved in the central carbon, amino acid, nucleotide, and lipid metabolism. Our findings reveal distinct alterations in plasma metabolite concentrations in response to acute or chronic morphine intake, and these changes were linked to the development of tolerance to morphine’s analgesic effects. We identified several metabolites that had been differentially affected by acute versus chronic morphine use, suggesting that metabolic changes may be mitigated by prolonged exposure to the drug. Morphine-tolerant mice showed a restoration of amino acid and glycolytic metabolites. Additionally, we conducted reconstructed metabolic network analysis on the first 30 VIP-ranked metabolites from the PLSDA of the saline, acute, and morphine-tolerant mice groups, which uncovered four interaction networks involving the amino acid metabolism, the TCA cycle, the glutamine-phenylalanine-tyrosine pathway, and glycolysis. These pathways were responsible for the metabolic differences observed following distinct morphine administration regimens. Overall, this study provides a valuable resource for future investigations into the role of metabolites in morphine-induced analgesia and associated effects following acute or chronic use in mice.

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“…As for IL-6, some studies have shown that inhibition of IL-6 can alleviate morphine tolerance [8]. In addition, IL-6 knockout mice can signi cantly alleviate the adverse reactions caused by long-term morphine treatments [37]. Understanding how the body controls the intensity of the secretion of in ammatory factors is a key focus of scientists studying morphine tolerance and OIH [38,39].…”

Section: Discussionmentioning

confidence: 99%

YTHDF1-TRAF6 pathway regulated neuroinflammation response contributed morphine tolerance and hyperalgesia in periaqueductal gray

Zhang

Ouyang

Chi

et al. 2022

Preprint

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Opioids like morphine have negative side effects such analgesia tolerance and morphine induced hyperalgesia (MIH), which is why their usage is restricted. Raising the dosage of morphine counteracts analgesic tolerance and MIH. Here, we discover that YTHDF1 and TNF receptor-associated factor 6 (TRAF6) expression, which are crucial for morphine analgesic tolerance and MIH. The m6A reader YTHDF1 positively controls the translation of TRAF6 mRNA, and chronic morphine treatments can enhance the m6A modification of TRAF6 mRNA. TRAF6 protein is drastically reduced by YTHDF1 knockdown, although TRAF6 mRNA level is unaffected. By reducing inflammatory markers such TNFα, IL-6, IL-1β and NF-κB, targeted reduction of YTHDF1 or suppression of TRAF6 activity in ventrolateral periaqueductal gray (vlPAG) slows the development of morphine analgesia tolerance and MIH. Our findings provide new insights into the mechanism by which YTHDF1 participates in morphine analgesia tolerance and MIH by regulating the inflammatory response involved in the expression of TRAF6 protein.

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Opioid Use in Murine Model Results in Severe Gastric Pathology that May Be Attenuated by Proton Pump Inhibition

Cited by 10 publications

References 53 publications

Opioid-induced dysbiosis of maternal gut microbiota during gestation alters offspring gut microbiota and pain sensitivity

Opioid-induced dysbiosis of maternal gut microbiota during gestation alters offspring gut microbiota and pain sensitivity

Changes in Plasma Metabolic Signature upon Acute and Chronic Morphine Administration in Morphine-Tolerant Mice

YTHDF1-TRAF6 pathway regulated neuroinflammation response contributed morphine tolerance and hyperalgesia in periaqueductal gray

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