Opioid Antagonists as a Potential Novel Class of Psychopharmacological Agents for Management of Anhedonia

The «anti-reward» system is closely linked to the functions of kappa-opioid (KOP) and nociceptin opioid (NOP) receptors. Their hyperactivation suppresses dopaminergic neurotransmission and leads to the development of anhedonia and negative affective states. Opioid antagonists aimed at supression of the antireward system represent a potentially novel class of psychopharmacological agents. Their action is directed not at stimulation of reward mechanisms, unlike traditional antidepressants, but at weakening hyperactive antireward processes. However, drugs currently undergoing clinical trials block only one type of receptor — KOP. This selective targeting may explain the disappointing results of phase 3 clinical trials of three kappa-opioid antagonists (aticaprant, navacaprant, ALKS-5461). A possible reason for the failure of KOP antagonists may be their lack of ability to prevent spontaneous (constitutive) receptor activation. Critically, if treatment-resistant depression results from increased constitutive activity of KOP receptors, then neutral KOP receptor antagonists are not ideal pharmacotherapeutic tools. KOP and NOP receptors are evolutionary paralogs formed by duplication of a single ancestor gene. They diverged during evolution but retained some degree of functional homology thus being able to compensate for each other’s loss of function. It can be assumed that simultaneous blockade of both KOP and NOP receptors would increase the clinical efficacy. Apparently, development of dual inverse agonists of both KOP and NOP receptors may prove the most promising. This review represents a theoretical basis for the emergence of a new psychopharmacological class — antagonists (blockers) of hyperactive opioidergic negative feedback loop within the endogenous reward system. We propose the name «hedoliberants» for this class (from Greek ‘hedone’ meaning pleasure and Latin ‘liberare’ meaning to free), reflecting the mechanism of liberation from pathological suppression of the endogenous reward system.