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Daily RC Article 94

Unravelling Opioids' Deadly Link: Gut Microbiota and Tolerance


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The most dangerous aspect of opioids is not that they are more addictive than other drugs. Rather, it’s that they are more deadly. This is because there are different classes and concentrations of µ-opioid receptors across the body –– and each area becomes tolerant of opioids at its own pace.

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Pharmacologist Hamid Akbarali at Virginia Commonwealth University says, “The problem is that you develop tolerance to different effects of opioids at different rates. You develop tolerance to the pain-relieving and euphoric effects a lot faster than you do to the respiratory depression.” With cocaine, death often occurs in people who haven’t used the drug for a while, and then start taking it again at their habitual dose –– they have lost their tolerance for the drug, which renders fatal a previously comfortable dose. Although this also happens with opioids, death can also occur as a result of the user’s more tolerant reward pathway demanding more of the drug than their respiratory pathway can cope with, which causes breathing and the heart to slow or stop.

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... Some of Akbarali’s work implicates bacteria that live in the gut, known collectively as the gut microbiota. “Chronic opioids change the gut bacteria,” he says. The drugs cause a breakdown of the epithelial barrier, which is the layer of cells that lines the digestive tract. As that layer degrades, bacteria move into the gut wall, which increases inflammation and, for reasons that are unclear, increases tolerance to opioids.

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In animal models, eliminating gut bacteria seems to negate opioid tolerance, which in turn decreases reward-seeking behaviour. Akbarali and his colleagues found that when they gave opioid-tolerant mice antibiotics before administering morphine, an opioid given for pain relief, the animals were able to withstand much more pain than they could otherwise, [because] their tolerance for morphine had decreased, and so they felt its effects more strongly.

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Anna Taylor, a pharmacologist at the University of Alberta in Canada, went one step further. When she gave antibiotics to opioid-naive mice, the animals showed symptoms similar to opioid withdrawal. … Taylor looked at how the composition of the gut microbiota changes during opioid exposure and withdrawal. “We found it changed twice: when you first gave the opioid, but again when they went through a period of withdrawal.”




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Taylor and her colleagues refined their experiments. They took mice that had never been exposed to morphine and gave them antibiotics to kill their gut microbiotas. They then transplanted gut microorganisms from the faeces of mice that were undergoing morphine withdrawal. Recipient mice exhibited behaviour that was consistent with opioid withdrawal… That the human gut has many more opioid receptors than it has receptors for any other addictive drug leads Taylor to conclude that the connection between the gut microbiota and symptoms of opioid addiction and withdrawal will probably be stronger than that of other drugs…

Opioids? unique danger lies not just in their addictiveness, but in their lethal impact on the body. Different opioid effects develop tolerance at varying rates, leading to fatal respiratory issues. Research suggests that gut bacteria changes induced by opioids might heighten tolerance and drive addiction. Studies on mice revealed that altering gut microbiota through antibiotics impacted tolerance levels and withdrawal symptoms, shedding light on the profound link between the gut and opioid-related effects.
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