Morphine tolerance is attenuated in germfree mice and reversed by probiotics, implicating the role of gut microbiome

Abstract

Prolonged exposure to opioids results in analgesic tolerance, drug overdose, and death. The mechanism underlying morphine analgesic tolerance still remains unresolved. We show that morphine analgesic tolerance was significantly attenuated in germfree (GF) and in pan-antibiotic−treated mice. Reconstitution of GF mice with naïve fecal microbiota reinstated morphine analgesic tolerance. We further demonstrated that tolerance was associated with microbial dysbiosis with selective depletion in Bifidobacteria and Lactobacillaeae. Probiotics, enriched with these bacterial communities, attenuated analgesic tolerance in morphine-treated mice. These results suggest that probiotic therapy during morphine administration may be a promising, safe, and inexpensive treatment to prolong morphine’s efficacy and attenuate analgesic tolerance. We hypothesize a vicious cycle of chronic morphine tolerance: morphine-induced gut dysbiosis leads to gut barrier disruption and bacterial translocation, initiating local gut inflammation through TLR2/4 activation, resulting in the activation of proinflammatory cytokines, which drives morphine tolerance.

The gut microbiome and its metabolites are necessary for morphine reward

“…Interestingly, while our studies showed marked effects of microbiome depletion on brain and behavior, we saw no effects of morphine treatment on microbiome composition. This is interesting as several other studies have shown family and species level changes in microbiome composition following prolonged morphine 32,33,37,38 . While morphine has known effects on gastrointestinal motility and function, it is noteworthy that these previously published studies used alternate dose and administration methods than our current work.…”

“…Previous work on the microbiome and opioids has shown that depletion of the gut microbiome, or germ-free status, reduces the formation of opioid tolerance 33,34 . While our regimen of morphine does not produce any symptoms of physical dependence or withdrawal, when considering the translational implications of gut-brain interactions in opioid use disorder, these studies are an important parallel to ours.…”

“…reports32,33,37,38 .There was no difference between H2O-Sal and H2O-Mor on measures of alpha diversity (observed OTUs: t(14) = 0.73, p = 0.47 and Shannon index: t(14) = 1.21, p = 0.25). Beta diversity assessed using an unweighted UniFrac dissimilarity matrix shows near complete overlap between samples in H2O-Sal and H2O-Mor groups (Fig.…”

“…While direct studies exploring the contribution of the gut microbiome to opioid reward or reinforcement have not been conducted, several pieces of evidence suggest interactions between the microbiome and some effects of opioids. Germ-free mice or mice with their microbiome knocked down via oral Abx do not develop tolerance to the antinociceptive effects of morphine 33,34 ; this effect is reversed by colonization of the gut with a microbiome from healthy animals 33 . Additionally, Abx has been shown to disrupt the neuronal ensembles normally activated by oxycodone administration and withdrawal 35 , suggesting that the microbiome mediates opioids' effects on both behavior and brain…”

¿Bacterias para la tolerancia analgésica a la morfina?

“…Es necesario entender los acontecimientos que conducen a los opioides a producir tolerancia analgésica, para así diseñar estrategias terapéuticas eficaces frente a este problema, para lo cual es imprescindible la realización de estudios preclínicos. En un trabajo publicado recientemente en Proceedings of the National Academy of Sciences of the USA, dirigido por la Profesora Sabita Roy (Universidad de Miami), se ha estudiado la relación entre la microbiota y la tolerancia a la analgesia morfínica en ratones, con resultados sorprendentes (8).…”