Evaluation of the therapeutic potential of exclusive antagonists of extrasynaptic NMDA receptors for treatment of opioid use disorders

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ABSTRACT Opioid use in the United States has been at epidemic proportions for over five years. Concerted efforts across the spectrum of political, social awareness, clinical and research initiatives have so far been unable to curb the rising rates of opioid use across the country. From the treatment standpoint, a number of novel therapies to alleviate the severe opioid withdrawal symptoms and/or reduce risk of relapse continue to be proposed. Memantine, an FDA-approved NMDA receptor antagonist, has shown encouraging results as an adjunct to existing opioid use therapies. Its therapeutic efficacy likely derives from its preferential binding to NMDA receptors located outside the synapse, since broad spectrum NMDA receptor antagonists are associated with multiple clinical side effects. Furthermore, pre-clinical literature suggests that extrasynaptic NMDARs are preferentially targeted by cocaine and alcohol, although opioid effects on this receptor population remain unknown. We designed a nanostructured version of memantine (AuM) that physically prevents its binding to synaptic NMDA receptors, but allows activation of extrasynaptic receptors with potency exceeding that of free memantine. In studies performed in different labs, AuM has been demonstrated to exclusive target extrasynaptic NMDA receptors while exhibiting pronounced neuropeptide effects in several neurological disease models. In this proposal we will use a pre-clinical model to evaluate AuM targeting of extrasynaptic NMDA receptors as treatment of opioid withdrawal symptoms, a hallmark of opioid use disorder and a major reason for high rates of relapse among chronic opioid users.