Archival ReportEffect of Chronic Delivery of the Toll-like Receptor 4 Antagonist (+)-Naltrexone on Incubation of Heroin Craving
Section snippets
Overview of the Behavioral Experiments
Using procedures similar to the ones described in the Supplemental Online Methods section in Supplement 1, we found that acute injections of the short-acting TLR4 antagonist (+)-naloxone (10 or 30 mg/kg, subcutaneous [SC]) had an inconsistent effect on cue-induced heroin seeking in extinction tests (3 hours) on withdrawal days 1 and 15 (F.R. Theberge, unpublished data). We also found in these pilot studies that twice daily repeated injections of (+)-naloxone (30 mg/kg) during the withdrawal
In Vitro Assays
Results from the target screening performed by Caliper Life Sciences showed that (+)-naltrexone displayed no significant activity at the 64 biological targets examined. The summary data in Table S1 in Supplement 1 show that (+)-naltrexone had greater than 10 μmol/L affinity for the receptors and ion channels tested and failed to exhibit significant inhibition of the enzymes tested. Figure 1 depicts the dose-response curves for (+) and (−) isomers of naltrexone in the binding assay for human
Discussion
We used (+)-naltrexone to study the role of TLR4 in incubation of heroin craving, operationally defined as time-dependent increases in cue-induced heroin seeking in extinction tests after withdrawal from self-administered heroin. We first performed in vitro binding experiments to determine the possibility of non-TLR4 effects of (+)-naltrexone and found that (+)-naltrexone had minimal activity at a number of biologically relevant targets, as well as low binding affinity to MOR. In the in vivo
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