The effect of gut microbiome on tolerance to morphine mediated antinociception in mice
Open accessAbstract
There is growing appreciation for the importance of gastrointestinal microbiota in many physiological and pathophysiological processes. While morphine and other narcotics are the most widely prescribed therapy for moderate to severe pain clinically, they have been noted to alter microbial composition and promote bacterial translocation to other tissues. Here we examined the pharmacodynamic properties of chronic morphine in mice following bacterial depletion with oral gavage of an antibiotic cocktail (ABX). ABX significantly reduced gut bacteria and prevented chronic morphine induced increases in gut permeability, colonic mucosal destruction, and colonic IL-1β expression. In addition, ABX prevented the development of antinociceptive tolerance to chronic morphine in both the tail-immersion and acetic acid stretch assays. Morphine tolerance was also reduced by oral vancomycin that has 0% bioavailability. These findings were recapitulated in primary afferent neurons isolated from dorsal root ganglia (DRG) innervating the lower gastrointestinal tract, wherein in-vivo administration of ABX prevented tolerance to morphine-induced hypoexcitability. Finally, though ABX repeatedly demonstrated an ability to prevent tolerance, we show that it did not alter susceptibility to precipitation of withdrawal by naloxone. Collectively, these finding indicate that the gastrointestinal microbiome is an important modulator of physiological responses induced by chronic morphine administration.
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Recent findings indicate that gut microbiota modulates physiological responses related to tolerance induced by chronic morphine administration.
“Recent findings indicate that gut microbiota modulates physiological responses related to tolerance induced by chronic morphine administration (179).”
From A Biopsychosocial Overview of the Opioid Crisis: Considering Nutrition and Gastrointestinal Health (2019) · cites this paper as [179]
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Cites
Changes of Intestinal Functions in Liver Cirrhosis
Fukui, H., & Wiest, R. (2016) · Inflammatory Intestinal Diseases · doi:10.1159/000444436 · Cited by 6,820 · see citing works
Gut microbiota in health and disease
Sekirov, I., Russell, S. L., Antunes, L. C. M., & Finlay, B. B. (2010) · Physiological Reviews · doi:10.1152/physrev.00045.2009 · Cited by 4,182 · see citing works
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 · see citing works
Bacteria activate sensory neurons that modulate pain and inflammation
Chiu, I. M., Heesters, B. A., Ghasemlou, N., Von Hehn, C. A., Zhao, F., Tran, J., Wainger, B., Strominger, A., Muralidharan, S., Horswill, A. R., et al. (2013) · Nature · doi:10.1038/nature12479 · Cited by 949 · see citing works
Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors
Rousseaux, C., Thuru, X., Gelot, A., Barnich, N., Neut, C., Dubuquoy, L., Dubuquoy, C., Merour, E., Geboes, K., Chamaillard, M., et al. (2007) · Nature Medicine · doi:10.1038/nm1521 · Cited by 793 · see citing works
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 531 · see citing works
An enteric virus can replace the beneficial function of commensal bacteria
Kernbauer, E., Ding, Y., & Cadwell, K. (2014) · Nature · doi:10.1038/nature13960 · Cited by 513 · see citing works
Sekirov, I., Tam, N. M., Jogova, M., Robertson, M. L., Li, Y., Lupp, C., & Finlay, B. B. (2008) · Infection and Immunity · doi:10.1128/iai.00319-08 · Cited by 483 · see citing works
Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation
Hill, D. A., Siracusa, M. C., Abt, M. C., Kim, B. S., Kobuley, D., Kubo, M., Kambayashi, T., LaRosa, D. F., Renner, E. D., Orange, J. S., et al. (2012) · Nature Medicine · doi:10.1038/nm.2657 · Cited by 468 · see citing works
Hill, D. A., Hoffmann, C., Abt, M. C., Du, Y., Kobuley, D. E., Kirn, T. J., Bushman, F. D., & Artis, D. (2009) · Mucosal Immunology · doi:10.1038/mi.2009.132 · Cited by 425 · see citing works
Gut microbial products regulate murine gastrointestinal motility via Toll-like receptor 4 signaling
Anitha, M., Vijay–Kumar, M., Sitaraman, S. V., Gewirtz, A. T., & Srinivasan, S. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.06.034 · Cited by 397 · see citing works
Parthasarathy, G., Chen, J., Chen, X., Chia, N., O'Connor, H. M., Wolf, P. G., Gaskins, H. R., & Bharucha, A. E. (2016) · Gastroenterology · doi:10.1053/j.gastro.2015.10.005 · Cited by 396 · see citing works
Hutchinson, M. R., Bland, S. T., Johnson, K. W., Rice, K. C., Maier, S. F., & Watkins, L. R. (2007) · The Scientific World JOURNAL · doi:10.1100/tsw.2007.230 · Cited by 359 · see citing works
Glia: novel counter-regulators of opioid analgesia
Watkins, L. R., Hutchinson, M. R., Johnston, I. N., & Maier, S. F. (2005) · Trends in Neurosciences · doi:10.1016/j.tins.2005.10.001 · Cited by 327 · see citing works
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 · see citing works
Croswell, A., Amir, E., Teggatz, P., Barman, M., & Salzman, N. H. (2009) · Infection and Immunity · doi:10.1128/iai.00006-09 · Cited by 272 · see citing works
Xu, D., Gao, J., Gillilland, M., Wu, X., Song, I., Kao, J. Y., & Owyang, C. (2014) · Gastroenterology · doi:10.1053/j.gastro.2013.10.026 · Cited by 271 · see citing works
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 · see citing works
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 · see citing works
Self-citationChen, Y., Geis, C., & Sommer, C. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.4170-07.2008 · Cited by 165 · see citing works
Malykhina, A. P., Qin, C., Meerveld, B. G., Foreman, R. D., Lupu, F., & Akbarali, H. I. (2006) · Neurogastroenterology & Motility · doi:10.1111/j.1365-2982.2006.00807.x · Cited by 137 · see citing works
Self-citationBabrowski, T., Holbrook, C., Moss, J., Gottlieb, L., Valuckaite, V., Zaborin, A., Poroyko, V., Liu, D. C., Zaborina, O., & Alverdy, J. C. (2012) · Annals of Surgery · doi:10.1097/sla.0b013e3182331870 · Cited by 129 · see citing works
Betrapally, N. S., Gillevet, P. M., & Bajaj, J. S. (2016) · Gastroenterology · doi:10.1053/j.gastro.2016.02.073 · Cited by 123 · see citing works
Meng, J., Banerjee, S., Li, D., Sindberg, G. M., Wang, F., Ma, J., & Roy, S. (2015) · Scientific Reports · doi:10.1038/srep10918 · Cited by 109 · see citing works
Morphine Tolerance in the Mouse Ileum and Colon
Ross, G. R., Gabra, B. H., Dewey, W. L., & Akbarali, H. I. (2008) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.108.143438 · Cited by 85 · see citing works
Self-citationEffect of commensals and probiotics on visceral sensitivity and pain in irritable bowel syndrome
Theodorou, V., Ait-Belgnaoui, A., Agostini, S., & Eutamene, H. (2014) · Gut Microbes · doi:10.4161/gmic.29796 · Cited by 83 · see citing works
Colonic inflammation increases Na+ currents in bladder sensory neurons
Malykhina, A. P., Qin, C., Foreman, R. D., et al. (2004) · Neuroreport · doi:10.1097/00001756-200412030-00008 · Cited by 59 · see citing works
Intestinal bacteria influence brain activity in healthy humans
Collins, S. M., & Bercik, P. (2013) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2013.76 · Cited by 59 · see citing works
Narcotic Use in Patients with Crohn's Disease
Cross, R., Wilson, K., & Binion, D. (2003) · American Journal of Gastroenterology · doi:10.1111/j.1572-0241.2005.00256.x · Cited by 53 · see citing works
Morphine Decreases Enteric Neuron Excitability via Inhibition of Sodium Channels
Smith, T. H., Grider, J. R., Dewey, W. L., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0045251 · Cited by 52 · see citing works
Self-citationImpaired Mucosal Barrier Function in the Small Intestine of the Cystic Fibrosis Mouse
Lisle, R. C. D., Mueller, R., & Boyd, M. (2011) · Journal of Pediatric Gastroenterology and Nutrition · doi:10.1097/mpg.0b013e318219c397 · Cited by 49 · see citing works
Avoiding the Vicious Cycle of Prolonged Opioid Use in Crohn's Disease
Jones, J., & Loftus, E. V. (2005) · The American Journal of Gastroenterology · doi:10.1111/j.1572-0241.2005.50803.x · Cited by 28 · see citing works
Nevado, R., Forcén, R., Layunta, E., Murillo, M. D., & Grasa, L. (2015) · Revista Española de Enfermedades Digestivas · doi:10.17235/reed.2015.3868/2015 · Cited by 27 · see citing works
Ross, G. R., Gade, A. R., Dewey, W. L., & Akbarali, H. I. (2011) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00171.2011 · Cited by 26 · see citing works
Self-citationPedigo, N. W., & Dewey, W. L. (1981) · Neuroscience Letters · doi:10.1016/0304-3940(81)90430-4 · Cited by 21 · see citing works
Self-citationChen, J., Gong, Boyi, Yan, & Qiao (2012) · Journal of Pain Research · doi:10.2147/jpr.s27751 · Cited by 11 · see citing works
Morphine dependence in single enteric neurons from the mouse colon requires deletion ofβ-arrestin2
Smith, T. H., Ngwainmbi, J., Hashimoto, A., et al. (2014) · Physiological Reports · doi:10.14814/phy2.12140 · Cited by 7 · see citing works
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Minerbi, A., Gonzalez, E., Brereton, N. J. B., Anjarkouchian, A., Dewar, K., Fitzcharles, M.-A., Chevalier, S., & Shir, Y. (2019) · Pain · doi:10.1097/j.pain.0000000000001640 · Cited by 220 · see citing works
Lee, K., Vuong, H. E., Nusbaum, D. J., Hsiao, E. Y., Evans, C. J., & Taylor, A. M. W. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-018-0211-9 · Cited by 172 · see citing works
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- Authors
- Kang, M., Mischel, R. A., Bhave, S., Komla, E., Cho, A., Huang, C., Dewey, W. L., & Akbarali, H. I.
- Affiliations
- Virginia Commonwealth University (US)
- Corresponding author
- Akbarali, Hamid I.
- Venue
- Scientific Reports
- Published
- 2017-02-17
- Volume
- 7
- Issue
- 1
- Pages
- 42658-42658
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5314392
- OpenAlex
- W2588163334
- Cited by
- 154
- References
- 37
- Citations by year
- 2026: 3 · 2025: 25 · 2024: 19 · 2023: 21 · 2022: 20 · 2021: 23 · 2020: 15 · 2019: 18 · 2018: 7 · 2017: 3
- FWCI
- 8.90
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute on Drug Abuse (R01DA024009, R01DA036975, P30DA033934, T32DA007027)
- National Institute of General Medical Sciences (R25GM090084)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- gut microbiota, morphine tolerance, antinociception, antibiotic depletion, intestinal permeability, colonic mucosa, IL-1β, dorsal root ganglia, primary afferent neurons, naloxone-precipitated withdrawal, opioid analgesia, bacterial translocation
- MeSH terms
- Gastrointestinal Microbiome, Analgesics, Opioid, Animals, Anti-Bacterial Agents, Cecum, Drug Tolerance, Ganglia, Spinal, Male, Morphine, Morphine Dependence, Naloxone, Narcotic Antagonists, Pain, Spleen, Stomach, Substance Withdrawal Syndrome, Mice, Dysbiosis
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