%0 Journal Article %A M. R. Hutchinson %A A. L. Northcutt %A T. Hiranita %A X. Wang %A S. S. Lewis %A J. Thomas %A K. van Steeg %A T. A. Kopajtic %A L. C. Loram %A C. Sfregola %A E. Galer %A N. E. Miles %A S. T. Bland %A J. Amat %A R. R. Rozeske %A T. Maslanik %A T. R. Chapman %A K. A. Strand %A M. Fleshner %A R. K. Bachtell %A A. A. Somogyi %A H. Yin %A J. L. Katz %A K. C. Rice %A S. F. Maier %A L. R. Watkins %T Opioid Activation of Toll-Like Receptor 4 Contributes to Drug Reinforcement %D 2012 %R 10.1523/JNEUROSCI.0684-12.2012 %J The Journal of Neuroscience %P 11187-11200 %V 32 %N 33 %X 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. %U https://www.jneurosci.org/content/jneuro/32/33/11187.full.pdf