Lack of Effects of Toll-Like Receptor 4 Antagonists on the Reinforcing Effects of Cocaine and Remifentanil

The toll like receptor 4 (TLR4) is expressed in glial cells and reacts to potential toxic entities. This activation triggers various inflammatory reactions. (+)-Naloxone and (+)naltrexone, dextrorotatory enantiomers of opioid receptor antagonists [respectively, (−)naloxone and (−)-naltrexone], have been demonstrated to dock to TLR4 using “in-silico ” models, and function as an antagonist at this site in vivo [1,2]. Recently, (+)-naloxone have been reported to antagonize self-administration of a μ-opioid agonist remifentanil [3]. Further, (+)-naltrexone blocked self-administration of a dopamine uptake inhibitor cocaine [4]. These findings suggested a “novel” TLR4-mediated mechanism underlying the reinforcing effects of drugs of abuse across pharmacological classes. A more recent study [5] has, however, indicated that the TLR4 hypothesis is less viable.