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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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Cites
Global patterns of 16S rRNA diversity at a depth of millions of sequences per sample
Caporaso, J. G., Lauber, C. L., Walters, W. A., Berg-Lyons, D., Lozupone, C., Turnbaugh, P. J., Fierer, N., & Knight, R. D. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1000080107 · Cited by 9,944
Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease
Sampson, T. R., Debelius, J. W., Thron, T., Janssen, S., Shastri, G. G., Ilhan, Z. E., Challis, C., Schretter, C. E., Rocha, S., Gradinaru, V., et al. (2016) · Cell · doi:10.1016/j.cell.2016.11.018 · Cited by 3,622
Host microbiota constantly control maturation and function of microglia in the CNS
Erny, D., Hrabě de Angelis, A. L., Jaitin, D., Wieghofer, P., Staszewski, O., David, E., Keren-Shaul, H., Mahlakoiv, T., Jakobshagen, K., Buch, T., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4030 · Cited by 3,569
Sudo, N., Chida, Y., Aiba, Y., Sonoda, J., Oyama, N., Yu, X., Kubo, C., & Koga, Y. (2004) · The Journal of Physiology · doi:10.1113/jphysiol.2004.063388 · Cited by 2,735
Zheng, P., Zeng, B., Zhou, C., Liu, M., Fang, Z., Xu, X., Zeng, L., Chen, J., Fan, S., Du, X., et al. (2016) · Molecular Psychiatry · doi:10.1038/mp.2016.44 · Cited by 2,023
Bercik, P., Denou, E., Collins, J., Jackson, W., Lu, J., Jury, J., Deng, Y., Blennerhassett, P., Macri, J., McCoy, K. D., et al. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.04.052 · Cited by 1,748
Gut/brain axis and the microbiota
Mayer, E. A., Tillisch, K., & Gupta, A. (2015) · Journal of Clinical Investigation · doi:10.1172/jci76304 · Cited by 1,503
Principles and clinical implications of the brain-gut-enteric microbiota axis
Rhee, S. H., Pothoulakis, C., & Mayer, E. A. (2009) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2009.35 · Cited by 1,342
Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring
Buffington, S. A., Di Prisco, G. V., Auchtung, T. A., Ajami, N. J., Petrosino, J. F., & Costa-Mattioli, M. (2016) · Cell · doi:10.1016/j.cell.2016.06.001 · Cited by 1,163
Stress & the gut-brain axis: Regulation by the microbiome
Foster, J. A., Rinaman, L., & Cryan, J. F. (2017) · Neurobiology of Stress · doi:10.1016/j.ynstr.2017.03.001 · Cited by 1,150
Kelly, J. R., Kennedy, P. J., Cryan, J. F., Dinan, T. G., Clarke, G., & Hyland, N. P. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00392 · Cited by 1,110
Dopamine neurons modulate neural encoding and expression of depression-related behaviour
Tye, K. M., Mirzabekov, J. J., Warden, M. R., Ferenczi, E. A., Tsai, H.-C., Finkelstein, J., Kim, S.-Y., Adhikari, A., Thompson, K. R., Andalman, A. S., et al. (2013) · Nature · doi:10.1038/nature11740 · Cited by 1,073
Fröhlich, E. E., Farzi, A., Mayerhofer, R., Reichmann, F., Jačan, A., Wagner, B., Zinser, E., Bordag, N., Magnes, C., Fröhlich, E., et al. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.02.020 · Cited by 720
Evidence that opioids may have toll-like receptor 4 and MD-2 effects
Hutchinson, M. R., Zhang, Y., Shridhar, M., Evans, J. H., Buchanan, M. M., Zhao, T. X., Slivka, P. F., Coats, B. D., Rezvani, N., Wieseler, J. L., et al. (2009) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2009.08.004 · Cited by 575
Depletion of Murine Intestinal Microbiota: Effects on Gut Mucosa and Epithelial Gene Expression
Reikvam, D. H., Erofeev, A. S., Sandvik, A., Grcic, V., Jahnsen, F. L., Gaustad, P., McCoy, K. D., Macpherson, A. J., Meza‐Zepeda, L. A., & Johansen, F. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017996 · Cited by 552
Quantitating the subtleties of microglial morphology with fractal analysis
Karperien, A., Ahammer, H., & Jelinek, H. F. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00003 · Cited by 541
Tynan, R. J., Naicker, S., Hinwood, M., Nalivaiko, E., Buller, K. M., Pow, D. V., Day, T. A., & Walker, F. R. (2010) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2010.02.001 · Cited by 531
Inflammation Effects on Motivation and Motor Activity: Role of Dopamine
Felger, J. C., & Treadway, M. T. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2016.143 · Cited by 474
Vasudeva, R., Rutkowski, M. D., & DeLeo, J. A. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-22-09980.2002 · Cited by 468
The involvement of glial cells in the development of morphine tolerance
Song, P., & Zhao, Z.-Q. (2001) · Neuroscience Research · doi:10.1016/s0168-0102(00)00226-1 · Cited by 445
Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl− homeostasis
Ferrini, F., Trang, T., Mattioli, T.-A. M., Laffray, S., Del’Guidice, T., Lorenzo, L.-É., Castonguay, A., Doyon, N., Zhang, W., Godin, A. G., et al. (2013) · Nature Neuroscience · doi:10.1038/nn.3295 · Cited by 441
Clinical Pharmacokinetics of Vancomycin
Matzke, G. R., Zhanel, G. G., & Guay, D. R. P. (1986) · Clinical Pharmacokinetics · doi:10.2165/00003088-198611040-00001 · Cited by 360
Neural substrates of opiate withdrawal
Koob, G. F., Maldonado, R. J., & Stinus, L. (1992) · Trends in Neurosciences · doi:10.1016/0166-2236(92)90171-4 · Cited by 356
Corder, G. F., Tawfik, V. L., Wang, D., Sypek, E. I., Low, S. A., Dickinson, J. R., Sotoudeh, C., Clark, J. D., Barres, B. A., Bohlen, C. J., et al. (2017) · Nature Medicine · doi:10.1038/nm.4262 · Cited by 354
LYTE, M., LI, W., OPITZ, N., GAYKEMA, R., & GOEHLER, L. (2006) · Physiology & Behavior · doi:10.1016/j.physbeh.2006.06.019 · Cited by 334
Yarandi, S., Peterson, D. A., Treisman, G. J., Moran, T. H., & Pasricha, P. J. (2016) · Journal of Neurogastroenterology and Motility · doi:10.5056/jnm15146 · Cited by 308
Hutchinson, M. R., Lewis, S. S., Coats, B. D., Skyba, D. A., Crysdale, N. Y., Berkelhammer, D. L., Brzeski, A., Northcutt, A. L., Vietz, C. M., Judd, C. M., et al. (2008) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2008.09.012 · Cited by 306
Goehler, L. E., Park, S. M., Opitz, N., Lyte, M., & Gaykema, R. P. A. (2008) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2007.08.009 · Cited by 287
Opioid activation of Toll-Like receptor 4 contributes to drug reinforcement
Hutchinson, M., Northcutt, A., Hiranita, T., Wang, X.-H., Lewis, S. S., Thomas, J., van Steeg, K., Kopajtic, T., Loram, L., Sfregola, C., et al. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.0684-12.2012 · Cited by 279
Alterations of the Host Microbiome Affect Behavioral Responses to Cocaine
Kiraly, D. D., Walker, D. M., Calipari, E. S., Labonté, B., Issler, O., Peña, C. J., Ribeiro, E., Russo, S. J., & Nestler, E. J. (2016) · Scientific Reports · doi:10.1038/srep35455 · Cited by 267
Banerjee, S., Sindberg, G., Wang, F., Meng, J., Sharma, U., Zhang, L., Dauer, P., Chen, C., Dalluge, J., Johnson, T., et al. (2016) · Mucosal Immunology · doi:10.1038/mi.2016.9 · Cited by 266
Raghavendra, V., Tanga, F. Y., & DeLeo, J. A. (2004) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300315 · Cited by 263
Thomsen, K. R., Whybrow, P. C., & Kringelbach, M. L. (2015) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2015.00049 · Cited by 256
Morphine induces changes in the gut microbiome and metabolome in a morphine dependence model
Wang, F., Meng, J., Zhang, L., Johnson, T., Chen, C., & Roy, S. (2018) · Scientific Reports · doi:10.1038/s41598-018-21915-8 · Cited by 238
Opioids and the gut: pharmacology and current clinical experience
Schepper, H. U. D., Cremonini, F., Park, M., & Camilleri, M. (2004) · Neurogastroenterology & Motility · doi:10.1111/j.1365-2982.2004.00513.x · Cited by 214
Meng, J., Yu, H., Ma, J., Wang, J., Banerjee, S., Charboneau, R., Barke, R. A., & Roy, S. (2013) · PLoS ONE · doi:10.1371/journal.pone.0054040 · Cited by 212
Acharya, C., Betrapally, N. S., Gillevet, P. M., Sterling, R. K., Akbarali, H., White, M. B., Ganapathy, D., Fagan, A., Sikaroodi, M., & Bajaj, J. S. (2017) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.13858 · Cited by 175
Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents
Burma, N. E., Bonin, R. P., Leduc‐Pessah, H., Baimel, C., Cairncross, Z. F., Mousseau, M., Shankara, J. V., Stemkowski, P. L., Baimoukhametova, D. V., Bains, J. S., et al. (2017) · Nature Medicine · doi:10.1038/nm.4281 · Cited by 154
The effect of gut microbiome on tolerance to morphine mediated antinociception in mice
Kang, M., Mischel, R. A., Bhave, S., Komla, E., Cho, A., Huang, C., Dewey, W. L., & Akbarali, H. I. (2017) · Scientific Reports · doi:10.1038/srep42658 · Cited by 154
Neurobiology of opioid dependence in creating addiction vulnerability
Evans, C. J., & Cahill, C. M. (2016) · F1000Research · doi:10.12688/f1000research.8369.1 · Cited by 146
Allostatic mechanisms of opioid tolerance beyond desensitization and downregulation
Cahill, C. M., Walwyn, W., Taylor, A. M. W., Pradhan, A. A. A., & Evans, C. J. (2016) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2016.08.002 · Cited by 122
Gutsy Moves: The Amygdala as a Critical Node in Microbiota to Brain Signaling
Cowan, C. S. M., Hoban, A. E., Ventura‐Silva, A. P., Dinan, T. G., Clarke, G. A., & Cryan, J. F. (2017) · BioEssays · doi:10.1002/bies.201700172 · Cited by 110
Taylor, A. M. W., Castonguay, A., Ghogha, A., Vayssiere, P., Pradhan, A. A. A., Xue, L., Mehrabani, S., Wu, J., Levitt, P., Olmstead, M. C., et al. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2015.221 · Cited by 109
Self-citationEfficacy of Treatments for Opioid-Induced Constipation: Systematic Review and Meta-analysis
Nee, J. W., Zakari, M., Sugarman, M. A., Whelan, J., Hirsch, W., Sultan, S., Ballou, S., Iturrino, J., & Lembo, A. J. (2018) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2018.01.021 · Cited by 91
Neuroinflammation—a co-occurring phenomenon linking chronic pain and opioid dependence
Cahill, C. M., & Taylor, A. M. W. (2017) · Current Opinion in Behavioral Sciences · doi:10.1016/j.cobeha.2016.12.003 · Cited by 84
Leri, F., Zhou, Y., Goddard, B., Cummins, E., & Kreek, M. J. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300927 · Cited by 61
Safety concerns with long-term opioid use
Harned, M. E., & Sloan, P. A. (2016) · Expert Opinion on Drug Safety · doi:10.1080/14740338.2016.1177509 · Cited by 48
Bhave, S. M., Gade, A. R., Kang, M., Hauser, K. F., Dewey, W. L., & Akbarali, H. I. (2017) · The FASEB Journal · doi:10.1096/fj.201601068r · Cited by 48
Zhou, Y., Leri, F., Ho, A., & Kreek, M. J. (2013) · Neurochemical Research · doi:10.1007/s11064-013-1091-3 · Cited by 27
Laorden, E. M., Hurlé, M. A., Milanés, M. V., Laorden, M. L., & Almela, P. (2012) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.112.193581 · Cited by 14
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“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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