TY - JOUR
T1 - Morphine tolerance is attenuated in germfree mice and reversed by probiotics, implicating the role of gut microbiome
AU - Zhang, Li
AU - Meng, Jingjing
AU - Ban, Yuguang
AU - Jalodia, Richa
AU - Chupikova, Irina
AU - Fernandez, Irina
AU - Brito, Nivis
AU - Sharma, Umakant
AU - Abreu, Maria T.
AU - Ramakrishnan, Sundaram
AU - Roy, Sabita
N1 - Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Germfree mice
KW - Gut dysbiosis
KW - Gut−immune−brain axis
KW - Morphine tolerance
UR - http://www.scopus.com/inward/record.url?scp=85068267439&partnerID=8YFLogxK
U2 - 10.1073/pnas.1901182116
DO - 10.1073/pnas.1901182116
M3 - Article
C2 - 31209039
AN - SCOPUS:85068267439
SN - 0027-8424
VL - 116
SP - 13523
EP - 13532
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 27
ER -