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|Title:||Opioid activation of toll-like receptor 4 contributes to drug reinforcement|
van Steeg, K.
|Citation:||Journal of Neuroscience, 2012; 32(33):11187-11200|
|M. R. Hutchinson... J. Thomas, K. van Steeg... A. A. Somogyi... et al.|
|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.|
|Keywords:||Nucleus Accumbens; Animals; Mice, Inbred BALB C; Mice, Transgenic; Mice; Rats; Rats, Sprague-Dawley; Hyperalgesia; Dopamine; Naloxone; Mitogen-Activated Protein Kinase 1; Analgesics, Opioid; Narcotic Antagonists; Self Administration; Microdialysis; Drug Administration Routes; Analysis of Variance; Conditioning, Operant; Reinforcement (Psychology); Pain Threshold; Reaction Time; Signal Transduction; Protein Binding; Phosphorylation; Dose-Response Relationship, Drug; Models, Molecular; Time Factors; Male; Toll-Like Receptor 4; Myeloid Differentiation Factor 88|
|Rights:||Copyright © 2012 the authors|
|Appears in Collections:||Pharmacology publications|
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