Troriluzole attenuates opioid intake, reinforcing efficacy, seeking behaviours, physical dependence and antinociceptive tolerance in rats

Background and Purpose Riluzole, approved for amyotrophic lateral sclerosis (ALS), has a glutamate‐modulating profile favourable for mitigating opioid addiction. It reduces neuronal glutamate release and enhances glutamate reuptake, offering advantages over agents that only increase glutamate reuptake. However, riluzole has pharmacokinetic liabilities that limit repurposing. To overcome these limitations, we designed and prepared the prodrug troriluzole (TRLZ), which retains the mechanistic profile of riluzole but with optimized metabolic and pharmacokinetic properties (e.g., higher oral bioavailability and less pharmacokinetic variability). As dysregulation of glutamate systems during opioid exposure contributes to adverse opioid effects, we tested the hypothesis that TRLZ would inhibit several opioid‐derived adverse effects in rats. Experimental Approach In male Long–Evans and Sprague–Dawley rats, effects of TRLZ on oxycodone self‐administration were investigated under fixed‐ratio and progressive‐ratio reinforcement schedules. Effects of TRLZ on food self‐administration were also investigated. TRLZ effects on cue‐induced reinstatement of oxycodone seeking, and on morphine‐induced physical dependence, antinociceptive tolerance and respiratory depression were also investigated. TRLZ was administered intraperitoneally. Key Results TRLZ dose‐dependently reduced oxycodone self‐administration, reinforcing efficacy and cue‐induced reinstatement of oxycodone seeking without affecting inactive lever responding. TRLZ, at high doses, also inhibited food self‐administration. TRLZ reduced naloxone‐precipitated withdrawal signs in morphine‐dependent rats and antinociceptive tolerance during repeated morphine exposure. TRLZ also attenuated morphine‐induced respiratory depression. Conclusions and Implications TRLZ, already in clinical trials for cerebellar ataxia, also reduced opioid taking and seeking as well as opioid‐derived adverse effects in rats, supporting further study in treating opioid use disorders and pain management.