The DOI matches its Crossref record; 114 of the 114 references it cites were found in a registry or an index.
The “Toll” of Opioid-Induced Glial Activation: Improving the Clinical Efficacy of Opioids by Targeting Glia
Open accessAbstract
Glial activation participates in the mediation of pain including neuropathic pain, due to release of neuroexcitatory, proinflammatory products. Glial activation is now known to occur in response to opioids as well. Opioid-induced glial activation opposes opioid analgesia and enhances opioid tolerance, dependence, reward and respiratory depression. Such effects can occur, not via classical opioid receptors, but rather via non-stereoselective activation of toll-like receptor 4 (TLR4), a recently recognized key glial receptor participating in neuropathic pain as well. This discovery identifies a means for separating the beneficial actions of opioids (opioid receptor mediated) from the unwanted side-effects (TLR4/glial mediated) by pharmacologically targeting TLR4. Such a drug should be a stand-alone therapeutic for treating neuropathic pain as well. Excitingly, with newly-established clinical trials of two glial modulators for treating neuropathic pain and improving the utility of opioids, translation from rats-to-humans now begins with the promise of improved clinical pain control.
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“The blockade of glial cell activation restored mesolimbic dopamine function using minocycline (Taylor et al., 2016), prevented withdrawal using various inhibitors of glial cell activation (Watkins et al., 2009), prevented the relapse of morphine-seeking behavior via the epigenetic reprogramming of interleukin-10 overexpression (Schwarz et al., 2011), and prevented incubation-induced heroin seeking”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Watkins et al., 2009
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In the citing paper
“The acute administration of opioids exerts anti-inflammatory effects (Eisenstein, 2019), whereas chronic opioid exposure activates microglia and astrocytes in the spinal cord (Watkins et al., 2009;Cahill et al., 2016) and central nervous system, including the VTA, NAc, frontal cortex, and periaqueductal gray (Hao et al., 2011;Taylor et al., 2016).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Watkins et al., 2009
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 Watkins et al, 2009
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Citations
Cites
1 retracted
Obata, K., Katsura, H., Miyoshi, K., Kondo, T., Yamanaka, H., Kobayashi, K., Dai, Y., Fukuoka, T., Akira, S., & Noguchi, K. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05353.x · Cited by 80
RetractedATP mediates rapid microglial response to local brain injury in vivo
Davalos, D., Grutzendler, J., Yang, G., Kim, J. V., Zuo, Y., Jung, S., Littman, D. R., Dustin, M. L., & Gan, W.-B. (2005) · Nature Neuroscience · doi:10.1038/nn1472 · Cited by 3,913
DAMPs, PAMPs and alarmins: all we need to know about danger
Bianchi, M. E. (2007) · Journal of Leukocyte Biology · doi:10.1189/jlb.0306164 · Cited by 2,794
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-citationVasudeva, R., Tanga, F. Y., & DeLeo, J. A. (2003) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.052407 · Cited by 797
Ledeboer, A., Sloane, E. M., Milligan, E. D., Frank, M. G., Mahony, J. H., Maier, S. F., & Watkins, L. R. (2005) · Pain · doi:10.1016/j.pain.2005.02.009 · Cited by 677
Self-citationGLIA: A novel drug discovery target for clinical pain
Watkins, L. R., & Maier, S. F. (2003) · Nature Reviews Drug Discovery · doi:10.1038/nrd1251 · Cited by 674
Self-citationNociceptors Are Interleukin-1β Sensors
Binshtok, A. M., Wang, H., Zimmermann, K., Amaya, F., Vardeh, D., Shi, L., Brenner, G. J., Ji, R., Bean, B. P., Woolf, C. J., et al. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.3795-08.2008 · Cited by 664
The 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
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-citation
Research works printed but not linked: 3
- [45]Hutchinson MR 2009 Novel toll-like receptor 4 activity of opioids: implications for opioid analgesia and dependence Journal of Neuroscience revision in review
- [46]Lewis SS 2009 Morphine-3-glucuronide cuases enhance pain through proinflammatory glial mechanisms Neuroscience in review
- [73]Lewis SS 2009 Constriction of the facial nerve leads to increased sensitivity to somatosensory and auditory stimuli: characterization of an inflammatory and glial component Proc Soc Neurosci in press
Cited by
Sorted by citations
Neuroinflammation and Central Sensitization in Chronic and Widespread Pain
Ji, R.-R., Nackley, A., Huh, Y., Terrando, N., & Maixner, W. (2018) · Anesthesiology · doi:10.1097/aln.0000000000002130 · Cited by 1,630
Glia and pain: Is chronic pain a gliopathy?
Ji, R., Berta, T., & Nedergaard, M. (2013) · Pain · doi:10.1016/j.pain.2013.06.022 · Cited by 1,193
Microglia in Pain: Detrimental and Protective Roles in Pathogenesis and Resolution of Pain
Chen, G., Zhang, Y., Qadri, Y. J., Serhan, C. N., & Ji, R. (2018) · Neuron · doi:10.1016/j.neuron.2018.11.009 · Cited by 801
Morphine 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
Self-citationHäuser, W., Ablin, J., Fitzcharles, M.-A., Littlejohn, G., Luciano, J. V., Usui, C., & Walitt, B. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.22 · Cited by 505
Metadata
- Authors
- Watkins, L. R., Hutchinson, M. R., Rice, K. C., & Maier, S. F.
- Affiliations
- University of Colorado Boulder (US)
- National Institutes of Health (US)
- Corresponding author
- Watkins, Linda R.
- Venue
- Trends in Pharmacological Sciences
- Publisher
- Elsevier BV
- Published
- 2009-11
- Volume
- 30
- Issue
- 11
- Pages
- 581-591
- ISSN
- 0165-6147 (ISSN-L)
- PMC
- PMC2783351
- OpenAlex
- W2103076324
- Cited by
- 438
- References
- 114
- Citations by year
- 2026: 14 · 2025: 17 · 2024: 8 · 2023: 11 · 2022: 17 · 2021: 72 · 2020: 21 · 2019: 28 · 2018: 32 · 2017: 23 · 2016: 35 · 2015: 26 · 2014: 29 · 2013: 24 · 2012: 30
- FWCI
- 17.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Trends in Pharmacological Sciences (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Funders
- Merck Company Foundation
- American Australian Association
- International Association for the Study of Pain
- National Institutes of Health
- U.S. Food and Drug Administration
- National Health and Medical Research Council
- National Medical Research Council
- National Institute on Alcohol Abuse and Alcoholism
- National Institute on Drug Abuse (DA017670, K02DA015642, DA024044, DA 015642, R01DA023132, R01DA017670, K05DA024044)
- National Institute of Dental and Craniofacial Research (DE017782, R01DE017782)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- TLR4, neuropathic pain, opioid tolerance, opioid use disorder, respiratory depression, opioid analgesia, neuroinflammation
- MeSH terms
- Analgesics, Opioid, Animals, Clinical Trials as Topic, Humans, Neuralgia, Neuroglia, Pain, Drug Delivery Systems, Toll-Like Receptor 4, Rats
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