Role of Gut Microbiota in Morphine-induced Analgesic Tolerance

Abstract

Prolonged exposure to opioids results in analgesic tolerance, drug overdose, and death. The mechanism underlying morphine analgesic tolerance still remains unresolved. Currently, there are studies focusing on the role of the gut microbiota and its interactions with gut and brain (the microbiota-gut-brain axis) in substance abuse, especially opioid abuse. The microbiota-gut-brain axis is a bidirectional communication between central nervous system and gastrointestinal system. Emerging literature provides evidence that the gut microbiota orchestrates neurogenesis, brain development and function, as well as blood-brain-barrier integrity, and host behavior through vagal afferents, gut hormones, cytokines, and microbial metabolites. Gut dysbiosis disrupts the homeostasis between brain and gut in neurodegenerative disorder, central nervous system injury, and exacerbates disease progression. In opioid abuse subjects, increased comorbidity and behavioral changes are found to be associated with impaired gut integrity and bacterial translocation. We show that morphine analgesic tolerance was significantly attenuated in germ-free (GF) and in pan-antibiotic-treated (ABX) 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 bacteria, attenuated analgesic tolerance in morphine-treated mice. These results suggest that probiotics 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 pro-inflammatory cytokines, which drives morphine tolerance.