Risk for opioid abuse is diminished by inhibiting aldehyde dehydrogenase-2 (ALDH-2) in rats

Abstract

Significant opiate addiction is known to follow prescribed opiate use for pain. There is a serious unmet need for non-addicting medications to prevent subsequent opiate addiction after a short period of opioid treatment for temporary pain. Recent evidence indicates that selective inhibition of aldehyde dehydrogenase-2 (ALDH-2) reduces drug-seeking and trained self-administration of alcohol, cocaine and nicotine, apparently by preventing a concomitant surge of dopamine in the ventral tegmental area (VTA) and nucleus accumbens (NAc). Activation of the same dopaminergic pathway is also implicated in opioid-induced reinforcement. Therefore, we asked whether the selective ALDH-2 inhibitor, ANS-6637, would attenuate opioid self-administration in drug-naïve rats for opioid self-administration. Rats received oral doses of ANS-6637 (9, 18, 36 or 72 mg/kg) or an equal volume of control vehicle 2 h before exposure to remifentanil and a light cue to accentuate self-administration over 5 consecutive days. Self-administration and the numbers of lever presses on both active and inactive levers were recorded. ANS-6637 significantly reduces remifentanil self-administration over 5 sessions of treatment in rats without prior exposure to remifentanil. We also confirm that the highest dose of ANS-6637 (72 mg/kg) used in this study did not prevent remifentanil-induced analgesia using a classic hot plate test. Thus, ANS-6637 significantly reduces of initial exposure to remifentanil self-administration without affecting desired analgesia. These preliminary observations suggest that ANS-6637 appears to have potential value as a non-addictive therapeutic agent to prevent abuse of commonly used opiates in initiating pain management.