Opioids are the gold standard in treating pain; however, their clinical use is impaired by the development of tolerance and hyperalgesia when used chronically. Moreover, prolonged opioid use can lead to negative affective states that exacerbate the emotional disturbances already present in the chronic pain population. This work shows that inflammation in the brain contributes to this negative affect, although the mechanism driving central inflammation remains unclear. Recent reports have shown that neuroinflammation observed in other psychiatric conditions can be caused by disruptions to gut microbiota along a poorly understood gut-brain signaling axis.

Chronic opioid treatment leads to neuroinflammation, hyperalgesia, and anhedonia. Recent studies in both humans and rodents show that disruption of the gut microbiota is also a consequence of opioid use. Now, a new study led by Anna Taylor, University of Alberta, Edmonton, Canada, shows a causal link between morphine-induced alterations in the gut microbiota and the symptoms of opioid dependence, and suggests that targeting those changes may help alleviate the adverse side effects of opioids.

Taylor and colleagues show that both sustained and intermittent morphine treatment altered the gut microbiota in mice. However, only intermittent morphine, which was interspaced by daily periods of morphine withdrawal, produced the microglia-driven neuroinflammation, hyperalgesia, and impaired reward processing that are associated with opioid use. Microbiota transfer from intermittent morphine-treated mice to opioid-naïve mice recapitulated those outcomes, suggesting a causal connection between an altered gut microbiota resulting from morphine use and the negative effects of the drug.

As Taylor further pursued the mechanisms of opioid-driven neuroinflammation, she noticed the growing list of behavioral disorders, including autism, schizophrenia, and depression, in which the gut microbiome was implicated. She noted that, much like opioids, changes in the microbiome influence neuronal signaling as well as immune cell activation in the brain. This raised the possibility that the microbiome could have a role in the adverse effects of opioids.

The researchers in Taylor’s group were also encouraged to investigate the gut microbiome because opioids have profound effects on gut motility, including constipation during prolonged opioid use, and diarrhea during opioid withdrawal; such changes in motility are known to impact microbiota composition. “Given this evidence, we thought it was a pretty sure-fire thing that opioids influencing the gut microbiome,” Taylor said. And first author Kevin Lee, University of California, Los Angeles, US, added, “We thought that perhaps the microbiome might have something to do with the negative effects of opioid treatment.”

Maintaining a healthy gut microbiome promotes not only gut health but also brain health .

The gut microbiota mediates reward and sensory responses associated with regimen-selective morphine dependence.
Lee K, Vuong HE, Nusbaum DJ, Hsiao EY, Evans CJ, Taylor AMW
Neuropsychopharmacology. 2018 Dec; 43(13):2606-2614.


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