(229) Revealing a Brain-Gut Microbiome Connection following Chronic Opioid Treatment

Abstract

Chronic opioid use is characterized by several phenotypic markers, including hyperalgesia and negative affect. We and other have shown previously that inflammation in the brain contributes to these behavioral symptoms, although the mechanism by which opioids drive central inflammation remains unclear. Recent reports have shown that neuroinflammation observed in other psychiatric conditions characterized by negative affect can be caused by disruptions to gut microbiota along a poorly understood gut-brain signaling axis. In this study, we explored how opioid use and cessation impacts the mouse gut microbiome. We hypothesized that opioid-induced changes in the gut microbiota influences inflammation-driven hyperalgesia and impaired reward behavior. Male adult C57Bl6/J mice were treated with either intermittent or sustained morphine. A separate group of animals treated with saline served as a control. Tail withdrawal and conditioned place preference were used to assess changes in evoked pain thresholds (hyperalgesia) and impaired reward, respectively. After 96 hours of morphine treatment, fecal samples were collected and processed for 16s rDNA sequencing. Manipulation of the gut microbiome was used to assess the causal relationship between the gut microbiome and opioid dependent behaviors. While both intermittent and sustained morphine treatment led to alterations in the gut microbiota composition, intermittent morphine treatment led to exacerbated inflammation, hyperalgesia, and negative affect. Depletion of the gut microbiota via antibiotic treatment led to a similar phenotypic outcome to opioid dependence, including central inflammation, morphine tolerance, and decreased negative affect. Recolonizing antibiotic-depleted animals with a control microbiota restored microglia to a resting phenotype, improved reward behavior, and blocked hyperalgesia. Recolonization with an opioid microbiota (isolated from mice treated with intermittent morphine), maintained the opioid-dependent phenotype. Our findings suggest that differing opioid regimens uniquely influence the gut microbiome, and that this process is causally related to the development of opioid dependent behaviors.