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Papers of the Week

Papers: 15 Jun 2019 - 21 Jun 2019

Animal Studies

2019 Jul 02

Proc Natl Acad Sci U S A



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


Zhang L, Meng J, Ban Y, Jalodia R, Chupikova I, Fernandez I, Brito N, Sharma U, Abreu MT, Ramakrishnan S, Roy S
Proc Natl Acad Sci U S A. 2019 Jul 02; 116(27):13523-13532.
PMID: 31209039.


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 and 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.