TY - JOUR T1 - Opioid Activation of Toll-Like Receptor 4 Contributes to Drug Reinforcement JF - The Journal of Neuroscience JO - J. Neurosci. SP - 11187 LP - 11200 DO - 10.1523/JNEUROSCI.0684-12.2012 VL - 32 IS - 33 AU - M. R. Hutchinson AU - A. L. Northcutt AU - T. Hiranita AU - X. Wang AU - S. S. Lewis AU - J. Thomas AU - K. van Steeg AU - T. A. Kopajtic AU - L. C. Loram AU - C. Sfregola AU - E. Galer AU - N. E. Miles AU - S. T. Bland AU - J. Amat AU - R. R. Rozeske AU - T. Maslanik AU - T. R. Chapman AU - K. A. Strand AU - M. Fleshner AU - R. K. Bachtell AU - A. A. Somogyi AU - H. Yin AU - J. L. Katz AU - K. C. Rice AU - S. F. Maier AU - L. R. Watkins Y1 - 2012/08/15 UR - http://www.jneurosci.org/content/32/33/11187.abstract N2 - 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. ER -