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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<jats:italic>TLR4<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>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<jats:italic>in silico<\/jats:italic>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.<\/jats:p>","DOI":"10.1523\/jneurosci.0684-12.2012","type":"journal-article","created":{"date-parts":[[2012,8,15]],"date-time":"2012-08-15T16:28:32Z","timestamp":1345048112000},"page":"11187-11200","source":"Crossref","is-referenced-by-count":283,"title":["Opioid Activation of Toll-Like Receptor 4 Contributes to Drug Reinforcement"],"prefix":"10.1523","volume":"32","author":[{"given":"M. R.","family":"Hutchinson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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