Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/73360
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dc.contributor.author | Hutchinson, M. | - |
dc.contributor.author | Northcutt, A. | - |
dc.contributor.author | Hiranita, T. | - |
dc.contributor.author | Wang, X. | - |
dc.contributor.author | Lewis, S. | - |
dc.contributor.author | Thomas, J. | - |
dc.contributor.author | van Steeg, K. | - |
dc.contributor.author | Kopajtic, T. | - |
dc.contributor.author | Loram, L. | - |
dc.contributor.author | Sfregola, C. | - |
dc.contributor.author | Galer, E. | - |
dc.contributor.author | Miles, N. | - |
dc.contributor.author | Bland, S. | - |
dc.contributor.author | Amat, J. | - |
dc.contributor.author | Rozeske, R. | - |
dc.contributor.author | Maslanik, T. | - |
dc.contributor.author | Chapman, T. | - |
dc.contributor.author | Strand, K. | - |
dc.contributor.author | Fleshner, M. | - |
dc.contributor.author | Bachtell, R. | - |
dc.contributor.author | et al. | - |
dc.date.issued | 2012 | - |
dc.identifier.citation | The Journal of Neuroscience, 2012; 32(33):11187-11200 | - |
dc.identifier.issn | 0270-6474 | - |
dc.identifier.issn | 1529-2401 | - |
dc.identifier.uri | http://hdl.handle.net/2440/73360 | - |
dc.description.abstract | Opioid action was thought to exert reinforcing effects solely via the initial agonism of opioid receptors. Here, we present evidence for an additional novel contributor to opioid reward: the innate immune pattern-recognition receptor, toll-like receptor 4 (TLR4), and its MyD88-dependent signaling. Blockade of TLR4/MD2 by administration of the nonopioid, unnatural isomer of naloxone, (+)-naloxone (rats), or two independent genetic knock-outs of MyD88-TLR4-dependent signaling (mice), suppressed opioid-induced conditioned place preference. (+)-Naloxone also reduced opioid (remifentanil) self-administration (rats), another commonly used behavioral measure of drug reward. Moreover, pharmacological blockade of morphine-TLR4/MD2 activity potently reduced morphine-induced elevations of extracellular dopamine in rat nucleus accumbens, a region critical for opioid reinforcement. Importantly, opioid-TLR4 actions are not a unidirectional influence on opioid pharmacodynamics, since TLR4−/− mice had reduced oxycodone-induced p38 and JNK phosphorylation, while displaying potentiated analgesia. Similar to our recent reports of morphine-TLR4/MD2 binding, here we provide a combination of in silico and biophysical data to support (+)-naloxone and remifentanil binding to TLR4/MD2. Collectively, these data indicate that the actions of opioids at classical opioid receptors, together with their newly identified TLR4/MD2 actions, affect the mesolimbic dopamine system that amplifies opioid-induced elevations in extracellular dopamine levels, therefore possibly explaining altered opioid reward behaviors. Thus, the discovery of TLR4/MD2 recognition of opioids as foreign xenobiotic substances adds to the existing hypothesized neuronal reinforcement mechanisms, identifies a new drug target in TLR4/MD2 for the treatment of addictions, and provides further evidence supporting a role for central proinflammatory immune signaling in drug reward. | - |
dc.description.statementofresponsibility | M. R. Hutchinson... J. Thomas, K. van Steeg... A. A. Somogyi... et al. | - |
dc.language.iso | en | - |
dc.publisher | Society for Neuroscience | - |
dc.rights | Copyright © 2012 the authors. Authors grant JNeurosci a license to publish their work and copyright remains with the author. Material published from 2010 to 2014 is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported License (CC-BY-NC-SA). | - |
dc.source.uri | http://dx.doi.org/10.1523/jneurosci.0684-12.2012 | - |
dc.subject | Nucleus Accumbens | - |
dc.subject | Animals | - |
dc.subject | Mice, Inbred BALB C | - |
dc.subject | Mice, Transgenic | - |
dc.subject | Mice | - |
dc.subject | Rats | - |
dc.subject | Rats, Sprague-Dawley | - |
dc.subject | Hyperalgesia | - |
dc.subject | Dopamine | - |
dc.subject | Naloxone | - |
dc.subject | Mitogen-Activated Protein Kinase 1 | - |
dc.subject | Analgesics, Opioid | - |
dc.subject | Narcotic Antagonists | - |
dc.subject | Self Administration | - |
dc.subject | Microdialysis | - |
dc.subject | Drug Administration Routes | - |
dc.subject | Analysis of Variance | - |
dc.subject | Conditioning, Operant | - |
dc.subject | Pain Threshold | - |
dc.subject | Reaction Time | - |
dc.subject | Signal Transduction | - |
dc.subject | Protein Binding | - |
dc.subject | Phosphorylation | - |
dc.subject | Dose-Response Relationship, Drug | - |
dc.subject | Models, Molecular | - |
dc.subject | Time Factors | - |
dc.subject | Male | - |
dc.subject | Toll-Like Receptor 4 | - |
dc.subject | Myeloid Differentiation Factor 88 | - |
dc.subject | Reinforcement, Psychology | - |
dc.title | Opioid activation of toll-like receptor 4 contributes to drug reinforcement | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1523/JNEUROSCI.0684-12.2012 | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/465423 | - |
dc.relation.grant | http://purl.org/au-research/grants/arc/DP110100297 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Hutchinson, M. [0000-0003-2154-5950] | - |
dc.identifier.orcid | Somogyi, A. [0000-0003-4779-0380] | - |
Appears in Collections: | Aurora harvest Pharmacology publications |
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File | Description | Size | Format | |
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hdl_73360.pdf | Published version | 2.04 MB | Adobe PDF | View/Open |
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