Effects of opioids on microbiome-gut-brain axis

With the emergence of the intestinal microbiome and its metabolites playing a major role in disease formation and prognosis, the number of studies in this field has been increasing substantially. The use of opioid drugs and the increase in their side effects that even can result in death have revealed the necessity of elucidating the mechanisms of tolerance development. Although there are many reasons for the tolerance that develops with chronic morphine use, dysbiosis of the intestinal microbiota remains the most significant topic in understanding the tolerance pathways. The systemic effects of the intestinal microbiota and the mechanisms by which it fulfills these functions have not been fully clarified. In the light of the current literature, disruption of the intestinal barrier integrity is considered to be the first step in the process, therefore maintaining the barrier integrity is becoming the focus of drug studies. In this study we used, in-vivo behavioral assays to show the effect of chronic morphine administration in the central nervous system (CNS), IL-18 expression as an indicator of intestinal barrier integrity, and ex-vivo experimental models to reveal the pathways related to this release. The results of the study showed that chronic morphine administration caused a decrease in nesting behavior scores. This effect was also confirmed by pain-induced behavioral tests. It has been shown that the intestinal microbiota disruption induced by vancomycin and butyric acid reduces nociceptive tolerance to morphine, but does not affect the tolerance developed in the CNS. It was concluded that chronic morphine administration increased interleukin (IL)- 18 expression in ileum tissue via the mu-opioid receptor, and IL-18 release, which plays a role in maintaining intestinal barrier integrity, may be mediated by enteric neurons. Ex-vivo studies have shown that IL-18 release may be mediated by changes in the gut microbiota. It is anticipated that this study may add a new perspective to understanding the mechanism of opioid tolerance, molecular pharmacology, and drug research.