Analgesia and Prevention of Opioid Self‐Administration by Agmatine‐Based Analogues

Abstract

Chronic pain is a debilitating condition that is a heightened health concern due to the concurrent pain and opioid epidemics. The currently available options for the treatment and management of chronic pain, opioids, are associated with risk of conversion to addiction and diversion from patients for whom use is intended. To this end, we have studied non-opioid interventions, specifically the inhibition of the glutamatergic system. The glutamatergic system is shown to play a central role in opioid addiction, therefore its inhibition has been shown to prevent the development of opioid-seeking behavior in a rodent model of drug-seeking. A decarboxylated form of L-arginine, agmatine, is able to prevent the development of fentanyl-seeking behavior in a model of mouse self-administration likely through its role as an N-methyl-D-aspartate antagonist. However, agmatine has shown limited penetration through the blood brain barrier (BBB) and a short systemic half-life, limiting its clinical utility. We have designed a strategically-substituted agmatine compound (SSA3) with the goal of improving its penetration through the BBB by increasing the lipophilicity of agmatine, potentially improving distribution across the BBB and increasing its half-life following systemic delivery. To this end, we have evaluated SSA3 as a more viable potential therapeutic for the treatment of opioid use disorders (OUD). Mice (F, 21-30g) were given access to operant chambers and allowed to press either for oral oxycodone reward or an inactive control. Daily, the mice were given either a pre-treatment of a strategically-substituted agmatine (SSA3) compound or vehicle control, i.p.. Daily lever-pressing was recorded as an indication of drug-seeking behavior. Additionally, this same cohort was allowed to lever press for food pellet reward following conclusion of oxycodone reinforcement. Area under the curve (AUC) was compared between SSA pre-treated and vehicle pre-treated groups. Pre-treatment with the SSA3 compound significantly decreased oxycodone seeking behavior, but had no impact on food-maintained responding. Additionally, SSA3 showed no impact on motor coordination or cardiovascular function, side effects of concern for glutamatergic compounds. These data indicate that a strategically-substituted agmatine compound is capable of significantly reducing opioid-seeking behavior with a wide therapeutic window, avoiding the motor impairment and cardiovascular impairment typical of drugs of this class. Our future work includes optimization of dosing regimen as well as modeling the prevention of opioid relapse.