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Opioid-Induced Glial Activation: Mechanisms of Activation and Implications for Opioid Analgesia, Dependence, and Reward
Open accessAbstract
This review will introduce the concept of toll-like receptor (TLR)-mediated glial activation as central to all of the following: neuropathic pain, compromised acute opioid analgesia, and unwanted opioid side effects (tolerance, dependence, and reward). Attenuation of glial activation has previously been demonstrated both to alleviate exaggerated pain states induced by experimental pain models and to reduce the development of opioid tolerance. Here we demonstrate that selective acute antagonism of TLR4 results in reversal of neuropathic pain as well as potentiation of opioid analgesia. Attenuating central nervous system glial activation was also found to reduce the development of opioid dependence, and opioid reward at a behavioral (conditioned place preference) and neurochemical (nucleus accumbens microdialysis of morphine-induced elevations in dopamine) level of analysis. Moreover, a novel antagonism of TLR4 by (+)- and (-)-isomer opioid antagonists has now been characterized, and both antiallodynic and morphine analgesia potentiating activity shown. Opioid agonists were found to also possess TLR4 agonistic activity, predictive of glial activation. Targeting glial activation is a novel and as yet clinically unexploited method for treatment of neuropathic pain. Moreover, these data indicate that attenuation of glial activation, by general or selective TLR antagonistic mechanisms, may also be a clinical method for separating the beneficial (analgesia) and unwanted (tolerance, dependence, and reward) actions of opioids, thereby improving the safety and efficacy of their use.
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“An emerging body of evidence suggests that activated glia and glia-derived neuroinflammatory mediators play an important role in drug reward, dependence, tolerance and analgesic properties (Hutchinson et al., 2007).”
From Stress- and Glucocorticoid-Induced Priming of Neuroinflammatory Responses: Potential Mechanisms of Stress-Induced Vulnerability to Drugs of Abuse (2011) · cites this paper as Hutchinson et al., 2007
In the citing paper
“There is an emerging evidence that glia and glia-derived neuroinflammatory mediators play key roles in the development of drug abuse.”
From Stress- and Glucocorticoid-Induced Priming of Neuroinflammatory Responses: Potential Mechanisms of Stress-Induced Vulnerability to Drugs of Abuse (2011) · cites this paper as Hutchinson et al., 2007
In the citing paper
“Importantly, we have also shown that morphine and other clinically relevant opioids (oxycodone and methadone) function as TLR4 agonists using TLR4 transfected human embryonic kidney (HEK-293) cells (Hutchinson et al., 2007).”
From Stress- and Glucocorticoid-Induced Priming of Neuroinflammatory Responses: Potential Mechanisms of Stress-Induced Vulnerability to Drugs of Abuse (2011) · cites this paper as Hutchinson et al., 2007
In the citing paper
“Moreover, an overwhelming amount of evidence demonstrates that within the CNS, opioid administration leads to the activation of microglia via a toll-like receptor (TLR)-4-dependent mechanism, and produces paradoxical aggravation of proinflammatory immune responses (Hutchinson et al, 2007;Watkins et al, 2009).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Hutchinson et al, 2007
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Citations
Cites
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Spinal Glia and Proinflammatory Cytokines Mediate Mirror-Image Neuropathic Pain in Rats
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Self-citationThe CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy
Tanga, F. Y., Nutile-McMenemy, N., & DeLeo, J. A. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501634102 · Cited by 634
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Cited by
Sorted by citations
Pathological and protective roles of glia in chronic pain
Milligan, E. D., & Watkins, L. R. (2008) · Nature reviews. Neuroscience · doi:10.1038/nrn2533 · Cited by 1,443
Self-citationPathological pain and the neuroimmune interface
Grace, P. M., Hutchinson, M. R., Maier, S. F., & Watkins, L. R. (2014) · Nature reviews. Immunology · doi:10.1038/nri3621 · Cited by 982
Self-citationIncidence, reversal, and prevention of opioid-induced respiratory depression
Dahan, A., Aarts, L., & Smith, T. W. (2010) · Anesthesiology · doi:10.1097/aln.0b013e3181c38c25 · Cited by 634
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
Self-citationMorphine activates neuroinflammation in a manner parallel to endotoxin
Wang, X., Loram, L. C., Ramos, K. M., de Jesus, A. J., Thomas, J., Cheng, K., Reddy, A., Somogyi, A. A., Hutchinson, M. R., Watkins, L. R., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1200130109 · Cited by 521
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Metadata
- Authors
- Hutchinson, M. R., Bland, S. T., Johnson, K. W., Rice, K. C., Maier, S. F., & Watkins, L. R.
- Affiliations
- University of Colorado Boulder (US)
- Avigen Inc., Alameda, CA, USA
- National Institute on Drug Abuse (US)
- Corresponding author
- Hutchinson, Mark R.
- ORCID
- Venue
- The Scientific World JOURNAL
- Publisher
- Wiley
- Published
- 2007
- Volume
- 7
- Pages
- 98-111
- ISSN
- 1537-744X (ISSN-L)
- PMC
- PMC5901235
- OpenAlex
- W2103801183
- Cited by
- 359
- References
- 61
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 14 · 2023: 11 · 2022: 14 · 2021: 12 · 2020: 18 · 2019: 19 · 2018: 26 · 2017: 21 · 2016: 24 · 2015: 20 · 2014: 25 · 2013: 19 · 2012: 24
- FWCI
- 2.42
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- The Scientific World JOURNAL (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institutes of Health (DA015642, DA017670, DE017782)
- National Health and Medical Research Council (DA015642, DA017670, DE017782)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- glial activation, TLR4, neuropathic pain, opioid analgesia, opioid tolerance, opioid use disorder, opioid reward, conditioned place preference, dopamine, nucleus accumbens, morphine
- MeSH terms
- Analgesics, Opioid, Animals, Humans, Neuroglia, Pain, Toll-Like Receptors
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