Cited by 438Pain Mechanisms and TreatmentsPain Management and Opioid UseNeuropeptides and Animal Physiology

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 access

Watkins, Linda R., Hutchinson, Mark R., Rice, Kenner C., Maier, Steven F.·2009·Trends in Pharmacological Sciences

DOI 10.1016/j.tips.2009.08.002PMC PMC2783351

Open this paper in CoChat — free account

Abstract

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1016/j.tips.2009.08.002

Cites

114 of 114 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

1 retracted

THIS ARTICLE HAS BEEN RETRACTED: Toll‐like receptor 3 contributes to spinal glial activation and tactile allodynia after nerve injury
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
Retracted
ATP 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-citation
Inhibition of Microglial Activation Attenuates the Development but Not Existing Hypersensitivity in a Rat Model of Neuropathy
Vasudeva, R., Tanga, F. Y., & DeLeo, J. A. (2003) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.052407 · Cited by 797
Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation
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-citation
GLIA: 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-citation
Nociceptors 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

Show all 114 references

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

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-citation
Fibromyalgia
Häuser, 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
Evidence for brain glial activation in chronic pain patients
Loggia, M. L., Chonde, D. B., Akeju, O., Arabasz, G., Catana, C., Edwards, R. R., Hill, E., Hsu, S., Izquierdo-Garcia, D., Ji, R.-R., et al. (2015) · Brain · doi:10.1093/brain/awu377 · Cited by 503
Importance of glial activation in neuropathic pain
Mika, J., Żychowska, M., Popiołek-Barczyk, K., Rojewska, E., & Przewłocka, B. (2013) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2013.01.072 · Cited by 463
The transition of acute postoperative pain to chronic pain: an integrative overview of research on mechanisms
Chapman, C. R., & Vierck, C. J. (2017) · The Journal of Pain · doi:10.1016/j.jpain.2016.11.004 · Cited by 423
Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia
Hutchinson, M. R., Shavit, Y., Grace, P. M., Rice, K. C., Maier, S. F., & Watkins, L. R. (2011) · Pharmacological Reviews · doi:10.1124/pr.110.004135 · Cited by 397
Self-citation
Evidence-Based Nonpharmacologic Strategies for Comprehensive Pain Care
Tick, H., Nielsen, A., Pelletier, K. R., Bonakdar, R. A., Simmons, S., Glick, R. M., Ratner, E. F., Lemmon, R., Wayne, P. M., & Zador, V. (2018) · EXPLORE · doi:10.1016/j.explore.2018.02.001 · Cited by 404
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
Self-citation
Loss of μ opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia
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
Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development
Koob, G. F. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000083 · Cited by 337
Opioid-Induced Tolerance and Hyperalgesia
Mercadante, S., Arcuri, E., & Santoni, A. (2019) · CNS Drugs · doi:10.1007/s40263-019-00660-0 · Cited by 330
Emerging role of Toll-like receptors in the control of pain and itch
Liu, T., Gao, Y., & Ji, R. (2012) · Neuroscience Bulletin · doi:10.1007/s12264-012-1219-5 · Cited by 312
The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain
Donvito, G., Nass, S. R., Wilkerson, J. L., Curry, Z. A., Schurman, L. D., Kinsey, S. G., & Lichtman, A. H. (2018) · Neuropsychopharmacology · doi:10.1038/npp.2017.204 · Cited by 301
Roles of reactive oxygen and nitrogen species in pain
Salvemini, D., Little, J. W., Doyle, T. M., & Neumann, W. L. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.01.026 · Cited by 311
The role of opioid receptors in immune system function
Eisenstein, T. K. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02904 · Cited by 286
Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse
Lacagnina, M. J., Rivera, P. D., & Bilbo, S. D. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2016.121 · Cited by 271
Acute Pain Management in Opioid-Tolerant Patients: A Growing Challenge
Huxtable, C. A., Roberts, L. J., Somogyi, A. A., & Macintyre, P. E. (2011) · Anaesthesia and Intensive Care · doi:10.1177/0310057x1103900505 · Cited by 230
The therapeutic potential of interleukin-10 in neuroimmune diseases
Kwilasz, A. J., Grace, P. M., Šerbedžija, P., Maier, S. F., & Watkins, L. R. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.10.020 · Cited by 249
Self-citation
Chapter 1. Neurocircuitry of Addiction
Koob, G. F., & Volkow, N. D. (2021) · American Psychiatric Association Publishing eBooks · doi:10.1176/appi.books.9781615373970.kb01 · Cited by 236
Blockade of Toll-Like Receptor 4 Attenuates Morphine Tolerance and Facilitates the Pain Relieving Properties of Morphine
Eidson, L. N., & Murphy, A. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.1609-13.2013 · Cited by 167
How Do Sensory Neurons Sense Danger Signals?
Donnelly, C. R., Ouyang, C., & Ji, R. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.07.008 · Cited by 200
Implications of central immune signaling caused by drugs of abuse: Mechanisms, mediators and new therapeutic approaches for prediction and treatment of drug dependence
Coller, J. K., & Hutchinson, M. R. (2012) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2012.01.008 · Cited by 186
Self-citation
Possible involvement of toll-like receptor 4/myeloid differentiation factor-2 activity of opioid inactive isomers causes spinal proinflammation and related behavioral consequences
Hutchinson, M. R., Lewis, S. S., Coats, B. D., Rezvani, N., Zhang, Y., Wieseler, J. L., Somogyi, A. A., Yin, H., Maier, S. F., Rice, K. C., et al. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.02.011 · Cited by 181
Self-citation
Stress-Induced Visceral Pain: Toward Animal Models of Irritable-Bowel Syndrome and Associated Comorbidities
Moloney, R. D., O’Mahony, S. M., Dinan, T. G., & Cryan, J. F. (2015) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2015.00015 · Cited by 171
Transition from Acute to Chronic Pain: Evaluating Risk for Chronic Postsurgical Pain
Wang, J. (2019) · Pain Physician · doi:10.36076/ppj/2019.22.479 · Cited by 155
Innate immune receptor Toll-like receptor 4 signalling in neuropsychiatric diseases
García‐Bueno, B., Caso, J. R., Madrigal, J. L. M., & Leza, J. C. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.02.013 · Cited by 157
Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse
Korpi, E. R., den Hollander, B., Farooq, U., Vashchinkina, E., Rajkumar, R., Nutt, D. J., Hyytiä, P., & Dawe, G. S. (2015) · Pharmacological Reviews · doi:10.1124/pr.115.010967 · Cited by 148
Evaluating the role of Toll-like receptors in diseases of the central nervous system
Carty, M., & Bowie, A. (2011) · Biochemical Pharmacology · doi:10.1016/j.bcp.2011.01.003 · Cited by 151
Targeting toll-like receptor-4 (TLR4)—an emerging therapeutic target for persistent pain states
Bruno, K. A., Woller, S. A., Miller, Y. I., Yaksh, T. L., Wallace, M. S., Beaton, G., & Chakravarthy, K. V. (2018) · Pain · doi:10.1097/j.pain.0000000000001306 · Cited by 139
Activation of Nuclear PPARγ Receptors by the Antidiabetic Agent Pioglitazone Suppresses Alcohol Drinking and Relapse to Alcohol Seeking
Stopponi, S., Somaini, L., Cippitelli, A., Cannella, N., Braconi, S., Kallupi, M., Ruggeri, B., Heilig, M. A., Demopulos, G. A., Gaitanaris, G., et al. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.12.010 · Cited by 136
Prenatal opioid exposure: The next neonatal neuroinflammatory disease
Jantzie, L. L., Maxwell, J. R., Newville, J., Yellowhair, T. R., Kitase, Y., Madurai, N. K., Ramachandra, S., Bakhireva, L. N., Northington, F. J., Gerner, G. J., et al. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.11.007 · Cited by 133
Remifentanil-induced postoperative hyperalgesia: current perspectives on mechanisms and therapeutic strategies
Santonocito, C., Noto, A., Crimi, C., & Sanfilippo, F. (2018) · Local and Regional Anesthesia · doi:10.2147/lra.s143618 · Cited by 127
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
Involvement of microglial P2X7 receptors and downstream signaling pathways in long-term potentiation of spinal nociceptive responses
Chu, Y., Zhang, Y., Zhang, Y., & Zhao, Z.-Q. (2010) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2010.06.001 · Cited by 117
Transition from acute to chronic pain
Feizerfan, A., & Sheh, G. (2014) · Continuing Education in Anaesthesia Critical Care & Pain · doi:10.1093/bjaceaccp/mku044 · Cited by 112
Morphine‐enhanced apoptosis in selective brain regions of neonatal rats
Bajic, D., Commons, K. G., & Soriano, S. G. (2013) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2013.02.009 · Cited by 111
Epigenetic imprinting by commensal probiotics inhibits the IL-23/IL-17 axis in an in vitro model of the intestinal mucosal immune system
Ghadimi, D., Helwig, U., Schrezenmeir, J., Heller, K. J., & de Vrese, M. (2012) · Journal of Leukocyte Biology · doi:10.1189/jlb.0611286 · Cited by 111
The discovery and development of analgesics: new mechanisms, new modalities
Burgess, G. M., & Williams, D. (2010) · Journal of Clinical Investigation · doi:10.1172/jci43195 · Cited by 109
A3 adenosine receptor agonist prevents the development of paclitaxel-induced neuropathic pain by modulating spinal glial-restricted redox-dependent signaling pathways
Janes, K., Esposito, E., Doyle, T. M., Cuzzocrea, S., Tosh, D. K., Jacobson, K. A., & Salvemini, D. (2014) · Pain · doi:10.1016/j.pain.2014.09.016 · Cited by 111
Inflammatory mediators of opioid tolerance: Implications for dependency and addiction
Eidson, L. N., & Murphy, A. Z. (2019) · Peptides · doi:10.1016/j.peptides.2019.01.003 · Cited by 108
Glial and neuroinflammatory targets for treating substance use disorders
Bachtell, R. K., Jones, J. D., Heinzerling, K. G., Beardsley, P. M., & Comer, S. D. (2017) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2017.08.003 · Cited by 116
Exploring the LPS/TLR4 signal pathway with small molecules
Peri, F., Piazza, M., Calabrese, V., Damore, G., & Cighetti, R. (2010) · Biochemical Society Transactions · doi:10.1042/bst0381390 · Cited by 102
Evidence that tricyclic small molecules may possess toll-like receptor and myeloid differentiation protein 2 activity
Hutchinson, M. R., Loram, L. C., Zhang, Y., Shridhar, M., Rezvani, N., Berkelhammer, D. L., Phipps, S., Foster, P. S., Landgraf, K., Falke, J. J., et al. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.03.067 · Cited by 102
Self-citation
Why is neuroimmunopharmacology crucial for the future of addiction research?
Hutchinson, M. R., & Watkins, L. R. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.05.039 · Cited by 100
Self-citation
Intrathecal cannabilactone CB2R agonist, AM1710, controls pathological pain and restores basal cytokine levels
Wilkerson, J. L., Gentry, K. R., Dengler, E. C., Wallace, J. A., Kerwin, A. A., Armijo, L. M., Kuhn, M. N., Thakur, G. A., Makriyannis, A., & Milligan, E. D. (2012) · Pain · doi:10.1016/j.pain.2012.02.015 · Cited by 99
Blockade of Toll-Like Receptors (TLR2, TLR4) Attenuates Pain and Potentiates Buprenorphine Analgesia in a Rat Neuropathic Pain Model
Jurga, A. M., Rojewska, E., Piotrowska, A., Makuch, W., Piłat, D., Przewłocka, B., & Mika, J. (2015) · Neural Plasticity · doi:10.1155/2016/5238730 · Cited by 99
Opioid‐Induced Central Immune Signaling: Implications for Opioid Analgesia
Grace, P. M., Maier, S. F., & Watkins, L. R. (2015) · Headache The Journal of Head and Face Pain · doi:10.1111/head.12552 · Cited by 104
Self-citation
Toll-Like Receptor 9 Is Required for Opioid-Induced Microglia Apoptosis
He, L., Li, H., Chen, L., Miao, J., Jiang, Y., Zhang, Y., Xiao, Z., Hanley, G., Li, Y., Zhang, X., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0018190 · Cited by 97
Pharmacological characterization of LPS and opioid interactions at the toll‐like receptor 4
Stevens, C., Aravind, S., Das, S., & Davis, R. (2012) · British Journal of Pharmacology · doi:10.1111/bph.12028 · Cited by 96
Neuronal and glial factors contributing to sex differences in opioid modulation of pain
Averitt, D. L., Eidson, L. N., Doyle, H. H., & Murphy, A. Z. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-018-0127-4 · Cited by 95
Palmitoylethanolamide in the Treatment of Chronic Pain Caused by Different Etiopathogenesis
Gatti, A., Lazzari, M., Gianfelice, V., Paolo, A. D., Sabato, E., & Sabato, A. F. (2012) · Pain Medicine · doi:10.1111/j.1526-4637.2012.01432.x · Cited by 101
Endomorphin analog analgesics with reduced abuse liability, respiratory depression, motor impairment, tolerance, and glial activation relative to morphine
Zadina, J. E., Nilges, M. R., Morgenweck, J., Zhang, X., Hackler, L., & Fasold, M. B. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.12.024 · Cited by 93
Toll-like Receptor Expression and Activation in Astroglia: Differential Regulation by HIV-1 Tat, gp120, and Morphine
El‐Hage, N., Podhaizer, E. M., Sturgill, J., & Hauser, K. F. (2011) · Immunological Investigations · doi:10.3109/08820139.2011.561904 · Cited by 96
Counter-Regulation of Opioid Analgesia by Glial-Derived Bioactive Sphingolipids
Muscoli, C., Doyle, T. M., Dagostino, C., Bryant, L., Chen, Z., Watkins, L. R., Ryerse, J. S., Bieberich, E., Neumman, W., & Salvemini, D. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.2391-10.2010 · Cited by 92
Self-citation
Shared Mechanisms for Opioid Tolerance and a Transition to Chronic Pain
Joseph, E. K., Reichling, D. B., & Levine, J. D. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.5530-09.2010 · Cited by 92
The activation of μ‐opioid receptor potentiates LPS‐induced NF‐kB promoting an inflammatory phenotype in microglia
Gessi, S., Borea, P. A., Bencivenni, S., Fazzi, D., Varani, K., & Merighi, S. (2016) · FEBS Letters · doi:10.1002/1873-3468.12313 · Cited by 91
Sterile Neuroinflammation and Strategies for Therapeutic Intervention
Banjara, M., & Ghosh, C. (2017) · International Journal of Inflammation · doi:10.1155/2017/8385961 · Cited by 92
Evidence for a role of heat shock protein-90 in toll like receptor 4 mediated pain enhancement in rats
Hutchinson, M. R., Ramos, K. M., Loram, L. C., Wieseler, J. L., Sholar, P. W., Kearney, J. J., Lewis, M. T., Crysdale, N. Y., Zhang, Y., Harrison, J. A., et al. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.09.046 · Cited by 87
Self-citation
Morphine amplifies mechanical allodynia via TLR4 in a rat model of spinal cord injury
Ellis, A., Grace, P. M., Wieseler, J. L., Favret, J., Springer, K., Skarda, B., Ayala, M. T., Hutchinson, M. R., Falci, S. P., Rice, K. C., et al. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.08.004 · Cited by 91
Self-citation
Reactive nitroxidative species and nociceptive processing: determining the roles for nitric oxide, superoxide, and peroxynitrite in pain
Little, J. W., Doyle, T. M., & Salvemini, D. (2010) · Amino Acids · doi:10.1007/s00726-010-0633-0 · Cited by 84
Chronic Morphine-Induced MicroRNA-124 Promotes Microglial Immunosuppression by Modulating P65 and TRAF6
Qiu, S., Feng, Y., LeSage, G., Zhang, Y., Stuart, C. A., He, L., Li, Y., Caudle, Y., Peng, Y., & Yin, D. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1400106 · Cited by 82
Intrathecal administration of antisense oligonucleotide against p38α but not p38β MAP kinase isoform reduces neuropathic and postoperative pain and TLR4-induced pain in male mice
Luo, X., Fitzsimmons, B., Mohan, A., Zhang, L., Terrando, N., Kordasiewicz, H. B., & Ji, R. (2017) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2017.11.007 · Cited by 82
Chronic exposure to corticosterone enhances the neuroinflammatory and neurotoxic responses to methamphetamine
Kelly, K. A., Miller, D. B., Bowyer, J. F., & O'Callaghan, J. P. (2012) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2012.07864.x · Cited by 83
Cannabinoid CB2receptor attenuates morphine‐induced inflammatory responses in activated microglial cells
Merighi, S., Gessi, S., Varani, K., Fazzi, D., Mirandola, P., & Borea, P. A. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.01948.x · Cited by 79
The Narcotic Bowel Syndrome: A Recent Update
Drossman, D. A., & Szigethy, E. (2014) · The American Journal of Gastroenterology Supplements · doi:10.1038/ajgsup.2014.6 · Cited by 78
Opioids: a two-faced Janus
Ahlbeck, K. (2011) · Current Medical Research and Opinion · doi:10.1185/03007995.2010.545379 · Cited by 78
Attenuation of microglial and IL-1 signaling protects mice from acute alcohol-induced sedation and/or motor impairment
Wu, Y. H., Lousberg, E. L., Moldenhauer, L. M., Hayball, J. D., Robertson, S. A., Coller, J. K., Watkins, L. R., Somogyi, A. A., & Hutchinson, M. R. (2011) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2011.01.012 · Cited by 78
Self-citation
Sex differences in mechanical allodynia: how can it be preclinically quantified and analyzed?
Nicotra, L. L., Tuke, J., Grace, P. M., Rolan, P. E., & Hutchinson, M. R. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00040 · Cited by 77
Self-citation
Opioids Should Not Be Used in Migraine
Tepper, S. J. (2012) · Headache The Journal of Head and Face Pain · doi:10.1111/j.1526-4610.2012.02140.x · Cited by 77
Robust spinal neuroinflammation mediates mechanical allodynia in Walker 256 induced bone cancer rats
Mao‐Ying, Q., Wang, X., Yang, C.-J., Xiu, L., Mi, W., Wu, G.-C., & Wang, Y. (2012) · Molecular Brain · doi:10.1186/1756-6606-5-16 · Cited by 76
Targeted Drug Delivery to Treat Pain and Cerebral Hypoxia
Ronaldson, P. T., & Davis, T. P. (2013) · Pharmacological Reviews · doi:10.1124/pr.112.005991 · Cited by 76
The PPARγ Agonist Pioglitazone Fails to Alter the Abuse Potential of Heroin, But Does Reduce Heroin Craving and Anxiety
Jones, J. D., Bisaga, A. M., Metz, V. E., Manubay, J. M., Mogali, S., Ciccocioppo, R., Madera, G., Doernberg, M., & Comer, S. D. (2018) · Journal of Psychoactive Drugs · doi:10.1080/02791072.2018.1508789 · Cited by 74
Targeting Opioid-Induced Hyperalgesia in Clinical Treatment: Neurobiological Considerations
Arout, C. A., Edens, E., Petrakis, I. L., & Sofuoglu, M. (2015) · CNS Drugs · doi:10.1007/s40263-015-0255-x · Cited by 80
Single-Cell Glia and Neuron Gene Expression in the Central Amygdala in Opioid Withdrawal Suggests Inflammation With Correlated Gut Dysbiosis
O’Sullivan, S. J., Malahias, E., Park, J., Srivastava, A., Reyes, B. A. S., Gorky, J., Vadigepalli, R., Bockstaele, E. J. V., & Schwaber, J. S. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00665 · Cited by 71
Current and Future Issues in the Development of Spinal Agents for the Management of Pain
Yaksh, T. L., Fisher, C. J., Hockman, T. M., & Wiese, A. J. (2016) · Current Neuropharmacology · doi:10.2174/1570159x14666160307145542 · Cited by 73
Discovery of a Novel Site of Opioid Action at the Innate Immune Pattern-Recognition Receptor TLR4 and its Role in Addiction
Jacobsen, J. H. W., Watkins, L. R., & Hutchinson, M. R. (2014) · International review of neurobiology · doi:10.1016/b978-0-12-801284-0.00006-3 · Cited by 72
Self-citation
Opioids and cancer
Wigmore, T., & Farquhar-Smith, P. W. (2016) · Current Opinion in Supportive and Palliative Care · doi:10.1097/spc.0000000000000208 · Cited by 72
Cannabinoid CB2 Agonist AM1710 Differentially Suppresses Distinct Pathological Pain States and Attenuates Morphine Tolerance and Withdrawal
Li, A.-L., Lin, X., Dhopeshwarkar, A., Thomaz, A. C., Carey, L. M., Liu, Y., Nikas, S. P., Makriyannis, A., Mackie, K., & Hohmann, A. G. (2018) · Molecular Pharmacology · doi:10.1124/mol.118.113233 · Cited by 69
Activation of adult rat CNS endothelial cells by opioid-induced toll-like receptor 4 (TLR4) signaling induces proinflammatory, biochemical, morphological, and behavioral sequelae
Grace, P. M., Ramos, K. M., Rodgers, K. M., Wang, X., Hutchinson, M. R., Lewis, M. T., Morgan, K. N., Kroll, J. L., Taylor, F. R., Strand, K. A., et al. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.09.020 · Cited by 67
Self-citation
Dynamic regulation of spinal pro-inflammatory cytokine release in the rat in vivo following peripheral nerve injury
Whitehead, K. J., Smith, C. G., Delaney, S. A., Curnow, J., Salmon, M., Hughes, J. P., & Chessell, I. P. (2009) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2009.12.007 · Cited by 67
Remifentanil Preconditioning Reduces Hepatic Ischemia–Reperfusion Injury in Rats via Inducible Nitric Oxide Synthase Expression
Yang, L., Tao, K., Liu, Y.-T., Cheung, C., Irwin, M. G., Wong, G. T. C., Lv, H., Song, J., Wu, F., & Yu, W. (2011) · Anesthesiology · doi:10.1097/aln.0b013e3182104956 · Cited by 67
Palmitoylethanolamide as adjunctive therapy in major depressive disorder: A double-blind, randomized and placebo-controlled trial
Ghazizadeh‐Hashemi, M., Ghajar, A., Shalbafan, M., Ghazizadeh‐Hashemi, F., Afarideh, M., Malekpour, F., Ghaleiha, A., Ardebili, M. E., & Akhondzadeh, S. (2018) · Journal of Affective Disorders · doi:10.1016/j.jad.2018.02.057 · Cited by 67
Naloxone-precipitated morphine withdrawal behavior and brain IL-1β expression: Comparison of different mouse strains
Liu, L., Coller, J. K., Watkins, L. R., Somogyi, A. A., & Hutchinson, M. R. (2011) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2011.03.016 · Cited by 66
Self-citation
Why mu‐opioid agonists have less analgesic efficacy in neuropathic pain?
Martínez‐Navarro, M., Maldonado, R. J., & Baños, J.-E. (2018) · European Journal of Pain · doi:10.1002/ejp.1328 · Cited by 65
The Contribution of the Descending Pain Modulatory Pathway in Opioid Tolerance
Lueptow, L. M., Fakira, A. K., & Bobeck, E. N. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00886 · Cited by 58
Naloxone inhibits immune cell function by suppressing superoxide production through a direct interaction with gp91 phox subunit of NADPH oxidase
Wang, Q., Zhou, H., Gao, H., Chen, S., Chu, C., Wilson, B. C., & Hong, J. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-32 · Cited by 65
Therapeutic Developments Targeting Toll‐like Receptor‐4‐Mediated Neuroinflammation
Li, J., Csakai, A., Jin, J., Zhang, F., & Yin, H. H. (2015) · ChemMedChem · doi:10.1002/cmdc.201500188 · Cited by 65
Persistent Peripheral Inflammation Attenuates Morphine-Induced Periaqueductal Gray Glial Cell Activation and Analgesic Tolerance in the Male Rat
Eidson, L. N., & Murphy, A. Z. (2013) · Journal of Pain · doi:10.1016/j.jpain.2012.12.010 · Cited by 65
Glial mechanisms underlying substance use disorders
Linker, K. E., Cross, S. J., & Leslie, F. M. (2019) · European Journal of Neuroscience · doi:10.1111/ejn.14163 · Cited by 64
Medication-overuse headache and opioid-induced hyperalgesia: A review of mechanisms, a neuroimmune hypothesis and a novel approach to treatment
Johnson, J. L., Hutchinson, M. R., Williams, D. B., & Rolan, P. E. (2012) · Cephalalgia · doi:10.1177/0333102412467512 · Cited by 63
Self-citation
Treatment of Complex Regional Pain Syndrome (CRPS) Using Low Dose Naltrexone (LDN)
Chopra, P., & Cooper, M. S. (2013) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-013-9451-y · Cited by 62
Targeting blood–brain Barrier Changes During Inflammatory Pain: an Opportunity for Optimizing CNS Drug Delivery
Ronaldson, P. T., & Davis, T. P. (2011) · Therapeutic Delivery · doi:10.4155/tde.11.67 · Cited by 60
Differential Spinal and Supraspinal Activation of Glia in a Rat Model of Morphine Tolerance
Jokinen, V., Sidorova, Y. A., Viisanen, H., Suleymanova, I., Tiilikainen, H., Li, Z., Lilius, T. O., Mätlik, K., Anttila, J. E., Airavaara, M., et al. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2018.01.048 · Cited by 60
Activation of JNK pathway in spinal astrocytes contributes to acute ultra–low-dose morphine thermal hyperalgesia
Sanna, M. D., Ghelardini, C., & Galeotti, N. (2015) · Pain · doi:10.1097/j.pain.0000000000000164 · Cited by 59
Chronic Administration of the Methylxanthine Propentofylline Impairs Reinstatement to Cocaine by a GLT-1-Dependent Mechanism
Reissner, K. J., Brown, R. M., Spencer, S. M., Tran, P. K., Thomas, C. A., & Kalivas, P. W. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.223 · Cited by 64
Identification of A3adenosine receptor agonists as novel non‐narcotic analgesics
Janes, K., Symons-Liguori, A. M., Jacobson, K. A., & Salvemini, D. (2016) · British Journal of Pharmacology · doi:10.1111/bph.13446 · Cited by 59
A deep convolutional neural network approach for astrocyte detection
Suleymanova, I., Balassa, T., Tripathi, S., Molnár, C., Saarma, M., Sidorova, Y. A., & Horváth, P. (2018) · Scientific Reports · doi:10.1038/s41598-018-31284-x · Cited by 58

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.
ORCID: Watkins, Linda R.
Hutchinson, Mark R.
Rice, Kenner C.
Maier, Steven F.
Venue: Trends in Pharmacological Sciences
Publisher: Elsevier BV
Published: 2009-11
Volume: 30
Issue: 11
Pages: 581-591
ISSN: 0165-6147 (ISSN-L)
DOI: 10.1016/j.tips.2009.08.002
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

The “Toll” of Opioid-Induced Glial Activation: Improving the Clinical Efficacy of Opioids by Targeting Glia

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks