RT Journal Article
SR Electronic
T1 Opioid Activation of Toll-Like Receptor 4 Contributes to Drug Reinforcement
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 11187
OP 11200
DO 10.1523/JNEUROSCI.0684-12.2012
VO 32
IS 33
A1 M. R. Hutchinson
A1 A. L. Northcutt
A1 T. Hiranita
A1 X. Wang
A1 S. S. Lewis
A1 J. Thomas
A1 K. van Steeg
A1 T. A. Kopajtic
A1 L. C. Loram
A1 C. Sfregola
A1 E. Galer
A1 N. E. Miles
A1 S. T. Bland
A1 J. Amat
A1 R. R. Rozeske
A1 T. Maslanik
A1 T. R. Chapman
A1 K. A. Strand
A1 M. Fleshner
A1 R. K. Bachtell
A1 A. A. Somogyi
A1 H. Yin
A1 J. L. Katz
A1 K. C. Rice
A1 S. F. Maier
A1 L. R. Watkins
YR 2012
UL http://www.jneurosci.org/content/32/33/11187.abstract
AB 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.