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

Li Zhang, Jingjing Meng, Yuguang Ban, Richa Jalodia, Irina Chupikova, Irina Fernandez, Nivis Brito, Umakant Sharma, Maria T. Abreu, Sundaram Ramakrishnan, Sabita Roy

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)13523-13532
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number27
StatePublished - 2019


  • Germfree mice
  • Gut dysbiosis
  • Gut−immune−brain axis
  • Morphine tolerance

ASJC Scopus subject areas

  • General


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