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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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García‐Cabrerizo, R., Carbia, C., O’Riordan, K. J., Schellekens, H., & Cryan, J. F. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15284 · Cited by 150
“Preliminary evidence indicates that drug-induced perturbations in the gut microbiota relate to reward response (Kiraly et al., 2016; Lee et al., 2018), which warrants for further research investigating the role of microbiome alterations in driving drug-seeking behaviour (Figure 4).”
BackgroundA potential role for the gut microbiome in substance use disorders
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Oxycodone in the Opioid Epidemic: High ‘Liking’, ‘Wanting’, and Abuse Liability
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Gut Microbiome in Anesthesiology and Pain Medicine
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“, 2012; Wohleb and Delpech, 2017), as well as in opioid-dependent states and particularly in states of withdrawal (Taylor et al., 2015; Lee et al., 2018).”
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The Gut Microbiome in Schizophrenia and the Potential Benefits of Prebiotic and Probiotic Treatment
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“Several experimental approaches in animal models have been used to study the influence of the GMB on the gut–brain axis, including fecal microbial transplantation [13,14], colonization with human [14,15] or synthetic [16] microbiota, manipulation of the GMB with antibiotics [13,17,18] and probiotics [19–21] and germ-f…”
MethodOpioid system influences gut-brain axis: Dysbiosis and related alterations
Rueda‐Ruzafa, L., Cruz, F., Cardona, D., Hone, A. J., Molina‐Torres, G., Sánchez‐Labraca, N., & Román, P. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.104928 · Cited by 65
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“Other studies reported that intermittent access to morphine in microbiome-depleted animals was associated with changes in hyperalgesia in the tail withdrawal test (Lee et al., 2018), but this was observed under conditions of 24-h spontaneous withdrawal.”
BackgroundDrugs and Bugs: The Gut-Brain Axis and Substance Use Disorders
Simpson, S., Mclellan, R., Wellmeyer, E., Matalon, F., & George, O. (2021) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-021-10022-7 · Cited by 63
“Morphine-treated animals also exhibited significant changes to secondary bile acid availability, which ensued after primary bile acids decrease following a reduction in Lactobacillus and Clostridium (Banerjee et al. 2016).”
InfluentialHong, H., Xu, L., Lu, Q., Huang, C., & Cui, Z. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1015035 · Cited by 61
Liao, K., Niu, F., Hu, G., Yang, L., Dallon, B. W., Villarreal, D. J., & Buch, S. J. (2020) · Journal of Extracellular Vesicles · doi:10.1002/jev2.12027 · Cited by 57
“These findings are in agreement with earlier reports describing thalamus as the preferred region of morphine action in the CNS (Emmers, 1984; Hutchinson et al., 2009; Lee et al., 2018; Matzeu, Zamora-Martinez, & Martin-Fardon, 2014).”
Kolli, U., Jalodia, R., Moidunny, S., Singh, P. K., Ban, Y. J., Tao, J., Cantu, G. N., Valdes, E., Ramakrishnan, S., & Roy, S. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2246184 · Cited by 60
“johnsonii NCC533 observed in morphine-treated samples corroborates with previous studies showing depletion of bacterial genus Lactobacillus in rodent models and human opioid studies.(10,11,18) Decrease in commensal bacteria might be facilitating the expansion of pathogenic bacteria as observed in morphine microbiome.”
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Hakimian, J. K., Dong, T. S., Barahona, J. A., Lagishetty, V., Tiwari, S., Azani, D., Barrera, M., Lee, S., Severino, A. L., Mittal, N., et al. (2019) · Nutrients · doi:10.3390/nu11081900 · Cited by 51
“This may be a result of the low, continuous levels and relatively short access (2 h) of opioid self-administered across the 27 days of the experiment, a regimen that is similar to continuous opioid exposure [67] that may not induce measurable neuro-inflammation.”
BackgroundRole of gut microbiota in neuropathy and neuropathic pain states: A systematic preclinical review
Pane, K., Boccella, S., Guida, F., Franzese, M., Maione, S., & Salvatore, M. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105773 · Cited by 51
Thomaz, A. C., Iyer, V., Woodward, T. J., & Hohmann, A. G. (2021) · Experimental Neurology · doi:10.1016/j.expneurol.2021.113787 · Cited by 49
Manipulation of Gut Microbiota as a Key Target for Crohn's Disease
Rashed, R. T., Valcheva, R. S., & Dieleman, L. A. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.887044 · Cited by 52
“and an increase in Ruminococcus spp (86).”
BackgroundInfluentialEvidence for Modulation of Substance Use Disorders by the Gut Microbiome: Hidden in Plain Sight
Angoa‐Pérez, M., & Kuhn, D. M. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000144 · Cited by 44
“It can be seen in Table 5 that NaB can either increase (Sanchis-Segura et al., 2009) or decrease (Legastelois et al., 2013) alcohol-induced locomotor sensitization.”
BackgroundMicrobiome and substances of abuse
Salavrakos, M., Leclercq, S., de Timary, P., & Dom, G. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.110113 · Cited by 45
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A Biopsychosocial Overview of the Opioid Crisis: Considering Nutrition and Gastrointestinal Health
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“However, it has been shown that antibiotic-treated rodents transplanted with saline microbiota have restored reward functioning (163).”
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The Gut Microbiome and Substance Use Disorder
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“Lee et al., 2018 Nicotine Nicotine altered the gut microbiota of C57BL/6 mice with sex-specific differences; nicotine led to decreased weight in males but not females; oxidative stress and DNA repair pathways were enriched in the microbiome after nicotine treatment; neurotransmitters (GABA) and…”
BackgroundHawkins, K. G., Casolaro, T. C., Brown, J. A., Edwards, D. A., & Wikswo, J. P. (2020) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.1870 · Cited by 35
“This is consistent with experiments with germ-free mice and bacterial depletion and probiotics in mice.(80,83,84) Stress, opioids, and injury can trigger central neuroimmune activation, which involves activation of the cells that provide an interface between blood and the nervous system, as well as parenchymal astrocy…”
ResultOpioid Use, Gut Dysbiosis, Inflammation, and the Nervous System
Jalodia, R., Abu, Y. F., Oppenheimer, M. R., Truitt, B., Meng, J., Chupikova, I., Tao, J., Ghosh, N., Dutta, R. K., Kolli, U., et al. (2022) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-021-10046-z · Cited by 40
Gut-derived bacterial LPS attenuates incubation of methamphetamine craving via modulating microglia
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Meckel, K. R., Simpson, S., Godino, A., Peck, E. G., Sens, J. P., Leonard, M. Z., George, O., Calipari, E. S., Hofford, R. S., & Kiraly, D. D. (2023) · Neuropsychopharmacology · doi:10.1038/s41386-023-01661-w · Cited by 35
Zhang, J., Deji, C., Fan, J., Chang, L., Miao, X., Xiao, Y., Zhu, Y., & Li, S. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.110058 · Cited by 34
Chen, Z., Lin, Y., Zhou, Q., Shilin, X., Li, C., Lin, R., Li, J., Chen, Y., Luo, C., & Mo, Z. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.112935 · Cited by 35
Unique Pharmacology, Brain Dysfunction, and Therapeutic Advancements for Fentanyl Misuse and Abuse
Han, Y., Cao, L., Yuan, K., Shi, J., Yan, W., & Lü, L. (2022) · Neuroscience Bulletin · doi:10.1007/s12264-022-00872-3 · Cited by 32
“Moreover, microbial metabolites, such as short-chain fatty acids, are reduced, and intestinal and blood-brain barrier integrity is disrupted after opioid use, which could modulate the development, maturation, and function of microglia and exacerbate the neuroimmune responses [87, 89, 90].”
BackgroundAbu, Y. F., Singh, S., Tao, J., Chupikova, I., Singh, P. K., Meng, J., & Roy, S. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2292224 · Cited by 32
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BackgroundInfluentialOn the Role of Peripheral Sensory and Gut Mu Opioid Receptors: Peripheral Analgesia and Tolerance
Fürst, S., Zádori, Z., Zádor, F., Király, K. P., Balogh, M., László, S. B., Hutka, B., Mohammadzadeh, A., Calabrese, C., Galambos, A. R., et al. (2020) · Molecules · doi:10.3390/molecules25112473 · Cited by 33
“Although there are some variabilities between the findings of the different studies, which may also result from the various treatment protocols [135], the administration of opioids is in general accompanied by the expansion of Staphylococcus and Enterococcus genera within the Firmicutes phylum and by reduced abundance…”
A gut (microbiome) feeling about addiction: Interactions with stress and social systems
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“However, recent research has revealed that depleting gut microbes results in reduced cocaine conditioning (García-Cabrerizo et al., 2023; Lee et al., 2018), as well as a decreased conditioning and sensitization to opioids like morphine (Hofford et al., 2021).”
Lucerne, K. E., Osman, A., Meckel, K. R., & Kiraly, D. D. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108598 · Cited by 27
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Abu, Y. F., Tao, J., Dutta, R. K., Yan, Y., Vitari, N., Kolli, U., & Roy, S. (2021) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-021-10019-2 · Cited by 28
The Microbiome–Gut–Brain Axis, a Potential Therapeutic Target for Substance-Related Disorders
Fu, X., Chen, T., Cai, J., Liu, B., Zeng, Y., & Zhang, X. (2021) · Frontiers in Microbiology · doi:10.3389/fmicb.2021.738401 · Cited by 29
Zhang, J., Yang, J., Yang, C., Chen, T., Wang, Z., Li, J., Qin, F., Deng, Q., & Zhang, X. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.00631 · Cited by 27
“Unique alterations in gut microbiota composition were noted following intermittent or sustained morphine administration (19).”
BackgroundRen, M., & Lotfipour, S. (2022) · Microorganisms · doi:10.3390/microorganisms10061127 · Cited by 28
“Preclinical studies have also shown an important role of gut microbiota in opioid-dependent behaviors, including reward, tolerance, and withdrawal [11,12,14].”
BackgroundResultSubstance use, microbiome and psychiatric disorders
Chivero, E. T., Sil, S., Kumar, M., & Buch, S. J. (2022) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2022.173432 · Cited by 26
Hofford, R. S., Meckel, K. R., Wiser, E. J., Wang, W., Sens, J. P., Kim, M., Godino, A., Lam, T. T., & Kiraly, D. D. (2023) · eNeuro · doi:10.1523/eneuro.0388-23.2023 · Cited by 28
“Recent work by our group and others has shown that alterations to the microbiome of rodents can affect cocaine (Kiraly et al., 2016; Lee et al., 2018) and opioid reward and reinforcement (Hofford et al., 2021b; Simpson et al., 2022), can in fl uence tolerance to opioids (Kang et al., 2017; Zhang et…”
BackgroundConsidering the Microbiome in Stress-Related and Neurodevelopmental Trajectories to Schizophrenia
Hoffman, K. W., Lee, J. J., Corcoran, C. M., Kimhy, D., Kranz, T. M., & Malaspina, D. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.00629 · Cited by 24
Endogenous Opiates and Behavior: 2018
Bodnar, R. J. (2020) · Peptides · doi:10.1016/j.peptides.2020.170348 · Cited by 22
Komla, E., Stevens, D. L., Zheng, Y., Zhang, Y., Dewey, W. L., & Akbarali, H. I. (2019) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.119.256941 · Cited by 22
“We have previously reported that NAP, a naltrexamine derivative, is a peripherally selective m-opioid receptor antagonist (Li et al., 2009; Yuan et al., 2012).”
BackgroundGarcía‐Cabrerizo, R., Barros-Santos, T., Campos, D., & Cryan, J. F. (2022) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2022.10.020 · Cited by 21
“In particular, it was reported that oral antibiotics decreased the conditioning response to cocaine (Lee et al., 2018), and reduced conditioning formation and sensitization to morphine (Hofford et al., 2021).”
Clinical and Preclinical Evidence for Gut Microbiome Mechanisms in Substance Use Disorders
Hofford, R. S., & Kiraly, D. D. (2023) · Biological Psychiatry · doi:10.1016/j.biopsych.2023.08.004 · Cited by 20
Gut microbiome associated dysbiosis: Limited regimens and expanding horizons of phage therapy
Singha, B., Rawat, B. S., Venkataraman, R., Nair, T., Rosenn, E. H., & Soni, V. (2023) · Aspects of Molecular Medicine · doi:10.1016/j.amolm.2023.100029 · Cited by 23
Role of microbes in the pathogenesis of neuropsychiatric disorders
Goswami, A., Wendt, F. R., Pathak, G. A., Tylee, D. S., Angelis, F. D., Lillo, A. D., & Polimanti, R. A. (2021) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2021.100917 · Cited by 21
Yang, Y. X., Xu, Z., Guo, J., Xiong, Z., & Hu, B. (2024) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2024.100763 · Cited by 23
“Opioids are notorious for causing constipation by reducing gut motility, potentially leading to an overgrowth of certain bacterial populations and a decrease in microbial diversity(Brown et al., 2021; Lee et al., 2018).”
BackgroundThe Impact of Alcohol-Induced Dysbiosis on Diseases and Disorders of the Central Nervous System
Liu, X., Vigorito, M., Huang, W., Khan, M. A. S., & Chang, S. L. (2021) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-021-10033-4 · Cited by 20
Ren, M., & Lotfipour, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms24010409 · Cited by 21
“Prior work showed that manipulation of the gut microbiota alters microglia morphology, a measure of neuroinflammation [27].”
BackgroundClinical neuroscience of addiction: what clinical psychologists need to know and why
Ray, L. A., & Grodin, E. N. (2021) · Annual Review of Clinical Psychology · doi:10.1146/annurev-clinpsy-081219-114309 · Cited by 18
Gut Microbiota‐Derived Extracellular Vesicles Influence Alcohol Intake Preferences in Rats
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“Alterations in gut microbiota composition have been clearly correlated with increased consumption of drugs of abuse, including morphine (Lee et al. 2018), cocaine (Kiraly et al. 2016; Tran et al. 2023) and alcohol (Ezquer et al. 2022; Ezquer et al. 2021; Reyes et al. 2020).”
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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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