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Papers of the Week

Papers: 9 Sep 2023 - 15 Sep 2023

Psychology, Translational

Human Studies, Pharmacology/Drug Development


2023 Sep 12

J Pharmacol Exp Ther


The Effects of Chronic Naltrexone on Reinstatement of Opioid-Induced Drug-Seeking Behavior and Antinociception


Withey SL, Bergman J, Paronis CA


Opioid addiction is a chronic relapsing disorder in which drug-seeking behavior during abstinence can be provoked by exposure to a µ-opioid receptor (MOR) agonist or opioid-associated cues. Opioid self-administration behavior in laboratory subjects can be reinstated by priming with MOR agonists or agonist-related stimuli, providing a procedure comparable to relapse. The opioid antagonist naltrexone has been forwarded as a pharmacologically effective approach to forestalling relapse and, in an extended-release formulation, has demonstrated some treatment success. However, chronic naltrexone treatment has not been extensively investigated in nonhuman subjects and aspects of its pharmacology remain uncertain. For example, the relative effectiveness of naltrexone in reducing the priming strength of opioid agonists differing in efficacy is not well understood. Here, using i.v self-administration and warm-water tail withdrawal procedures, we investigated changes in the direct reinforcing effects of oxycodone and in the priming strength and antinociceptive effects of opioid agonists in squirrel monkeys (n=4) during chronic treatment with naltrexone (0.2mg/kg/day). Results show that naltrexone produced: 1) a ten-fold rightward shift in the dose-response function for the reinforcing effects of oxycodone, and 2) in reinstatement and antinociception experiments, comparable rightward shifts in the dose-response functions for higher-efficacy MOR agonists (methadone, heroin, oxycodone) but rightward and downward shifts in the dose-response functions for lower-efficacy MOR agonists (buprenorphine, nalbuphine, butorphanol). These results suggest that, while chronic naltrexone should be effective in forestalling relapse following exposure to lower- and higher-efficacy agonists, the inability of lower-efficacy agonists to surmount naltrexone antagonism may complicate the prescription of opioids for pain. Though naltrexone is used in the treatment of OUD, its ability to reduce the priming strength of opioid agonists has not been extensively investigated. Here we show that chronic naltrexone treatment induces rightward shifts in the reinstatement and antinociceptive properties of higher efficacy opioid agonists, but rightward and downward shifts for lower efficacy opioid agonists, suggesting lower efficacy agonists may not surmount naltrexone-induced antagonism of these two effects and that perhaps naltrexone offers greater protection against lower efficacy agonists.