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The gut microbiota mediates reward and sensory responses associated with regimen-selective morphine dependence
Open accessAbstract
Opioid use for long-term pain management is limited by adverse side effects, such as hyperalgesia and negative affect. Neuroinflammation in the brain and spinal cord is a contributing factor to the development of symptoms associated with chronic opioid use. Recent studies have described a link between neuroinflammation and behavior that is mediated by a gut-brain signaling axis, where alterations in indigenous gut bacteria contribute to several inflammation-related psychopathologies. As opioid receptors are highly expressed within the digestive tract and opioids influence gut motility, we hypothesized that systemic opioid treatment will impact the composition of the gut microbiota. Here, we explored how opioid treatments, and cessation, impacts the mouse gut microbiome and whether opioid-induced changes in the gut microbiota influences inflammation-driven hyperalgesia and impaired reward behavior. Male C57Bl6/J mice were treated with either intermittent or sustained morphine. Using 16S rDNA sequencing, we describe changes in gut microbiota composition following different morphine regimens. Manipulation of the gut microbiome was used to assess the causal relationship between the gut microbiome and opioid-dependent behaviors. Intermittent, but not sustained, morphine treatment was associated with microglial activation, hyperalgesia, and impaired reward response. Depletion of the gut microbiota via antibiotic treatment surprisingly recapitulated neuroinflammation and sequelae, including reduced opioid analgesic potency and impaired cocaine reward following intermittent morphine treatment. Colonization of antibiotic-treated mice with a control microbiota restored microglial activation state and behaviors. Our findings suggest that differing opioid regimens uniquely influence the gut microbiome that is causally related to behaviors associated with opioid dependence.
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“Vitamin and mineral deficiencies associated with opioid addiction have been well-described (160–165).”
From A Biopsychosocial Overview of the Opioid Crisis: Considering Nutrition and Gastrointestinal Health (2019) · cites this paper as [163]
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“However, it has been shown that antibiotic-treated rodents transplanted with saline microbiota have restored reward functioning (163).”
From A Biopsychosocial Overview of the Opioid Crisis: Considering Nutrition and Gastrointestinal Health (2019) · cites this paper as [163]
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Global patterns of 16S rRNA diversity at a depth of millions of sequences per sample
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Cryan, J. F., O'Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F. S., Boehme, M., Codagnone, M. G., Cussotto, S., Fulling, C., Golubeva, A. V., et al. (2019) · Physiological Reviews · doi:10.1152/physrev.00018.2018 · Cited by 5,286
Pain regulation by gut microbiota: molecular mechanisms and therapeutic potential
Guo, R., Chen, L., Xing, C., & Liu, T. (2019) · British Journal of Anaesthesia · doi:10.1016/j.bja.2019.07.026 · Cited by 420
Matson, V., Chervin, C. S., & Gajewski, T. F. (2021) · Gastroenterology · doi:10.1053/j.gastro.2020.11.041 · Cited by 385
Psychotropics and the Microbiome: a Chamber of Secrets…
Cussotto, S., Clarke, G. A., Dinan, T. G., & Cryan, J. F. (2019) · Psychopharmacology · doi:10.1007/s00213-019-5185-8 · Cited by 176
“In a different study in mice, both intermittent and sustained morphine administration influenced the gut microbiome in a way that was causally related to behaviours associated with opioid dependence (Lee et al. 2018).”
BackgroundZhang, L., Meng, J., Ban, Y. J., Jalodia, R., Chupikova, I., Fernández, I., Brito, N., Sharma, U., Abreu, M. T., Ramakrishnan, S., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1901182116 · Cited by 164
“Studies have shown that morphine-induced gut dysbiosis was causally correlated with impaired cocaine-conditioned place preference and morphine hyperalgesia by modulating microglial activation (31).”
Background
Metadata
- Authors
- Lee, K., Vuong, H. E., Nusbaum, D. J., Hsiao, E. Y., Evans, C. J., & Taylor, A. M. W.
- Affiliations
- University of California, Los Angeles (US)
- University of Alberta (CA)
- Corresponding author
- Taylor, Anna M. W.
- ORCID
- Venue
- Neuropsychopharmacology
- Published
- 2018-09-10
- Volume
- 43
- Issue
- 13
- Pages
- 2606-2614
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC6224506
- OpenAlex
- W2890990778
- Cited by
- 172
- References
- 50
- Citations by year
- 2026: 6 · 2025: 19 · 2024: 19 · 2023: 26 · 2022: 34 · 2021: 26 · 2020: 26 · 2019: 15 · 2018: 1
- FWCI
- 6.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alfred P. Sloan Foundation
- American Pain Society
- National Institute of Mental Health (F31MH090749)
- National Institute on Drug Abuse (P50DA005010, DA 005010, K99DA040016)
- National Institute of General Medical Sciences (K12GM106996)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Opioid Use Disorder Treatment
- Keywords
- gut microbiota, morphine dependence, opioid use disorder, neuroinflammation, microglial activation, hyperalgesia, opioid reward, cocaine reward, gut-brain axis, antibiotic-induced microbiota depletion, chronic opioid use
- MeSH terms
- Gastrointestinal Microbiome, Analgesics, Opioid, Animals, Intestinal Absorption, Male, Mice, Inbred C57BL, Morphine, Morphine Dependence, Reward, Mice
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