Elsevier

Biological Psychiatry

Volume 73, Issue 8, 15 April 2013, Pages 729-737
Biological Psychiatry

Archival Report
Effect of Chronic Delivery of the Toll-like Receptor 4 Antagonist (+)-Naltrexone on Incubation of Heroin Craving

https://doi.org/10.1016/j.biopsych.2012.12.019Get rights and content

Background

Recent evidence implicates toll-like receptor 4 (TLR4) in opioid analgesia, tolerance, conditioned place preference, and self-administration. Here, we determined the effect of the TLR4 antagonist (+)-naltrexone (a μ-opioid receptor inactive isomer) on the time-dependent increases in cue-induced heroin seeking after withdrawal (incubation of heroin craving).

Methods

In an initial experiment, we trained rats for 9 hours per day to self-administer heroin (.1 mg/kg/infusion) for 9 days; lever presses were paired with a 5-second tone-light cue. We then assessed cue-induced heroin seeking in 30-minute extinction sessions on withdrawal day 1; immediately after testing, we surgically implanted rats with Alzet minipumps delivering (+)-naltrexone (0, 7.5, 15, 30 mg/kg/day, subcutaneous) for 14 days. We then tested the rats for incubated cue-induced heroin seeking in 3-hour extinction tests on withdrawal day 13.

Results

We found that chronic delivery of (+)-naltrexone via minipumps during the withdrawal phase decreased incubated cue-induced heroin seeking. In follow-up experiments, we found that acute injections of (+)-naltrexone immediately before withdrawal day 13 extinction tests had no effect on incubated cue-induced heroin seeking. Furthermore, chronic delivery of (+)-naltrexone (15 or 30 mg/kg/day) or acute systemic injections (15 or 30 mg/kg) had no effect on ongoing extended access heroin self-administration. Finally, in rats trained to self-administer methamphetamine (.1 mg/kg/infusion, 9 hours/day, 9 days), chronic delivery of (+)-naltrexone (30 mg/kg/day) during the withdrawal phase had no effect on incubated cue-induced methamphetamine seeking.

Conclusions

The present results suggest a critical role of TLR4 in the development of incubation of heroin, but not methamphetamine, 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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