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.
Rising rates of the opioid use despite a concerted effort to address the opioid epidemic in the United States urge the development and testing of novel therapeutic approaches. Memantine, an FDA-approved antagonist of NMDA receptors, was shown to suppress symptoms of opioid withdrawal and relapse when used at low concentrations and together with existing opioid use treatments. The full extent of potential therapeutic effects of memantine remains undetermined, because higher concentrations of memantine trigger serious side effects due to undesirable inhibition of synaptic NMDA receptors. We propose that restricting the interaction of memantine to a limited population of NMDA receptors in the brain using a nanobiological approach will dramatically enhance its therapeutic efficacy and help to treat opioid use disorders more efficiently.