SUMMARY The objective of our proposal is to demonstrate that the restoration of respiratory mechanics and of the metabolism by low doses of the central alpha-2 agonist dexmedetomidine results in an increase in ventilation and prevents the fatal outcome of an opioid overdose. Death by opioid overdose is the consequence of an acute respiratory failure mediated by a direct and indirect inhibition of the medullary respiratory neurons. This inhibition is associated with immediate and prolonged tetanic contractions of the inspiratory and expiratory muscles and an increase in upper-airway resistance that impede respiratory movements for hours. Opioid-induced muscle “rigidity” is produced via neurons in the locus coeruleus and can be suppressed by central alpha-2 agonist agents. Our preliminary results, obtained in sedated and non- sedated rats, show that infusion of low doses of the central alpha-2 agonist dexmedetomidine restores chest wall compliance and suppresses the hypermetabolism produced by fentanyl-induced muscle rigidity, while increasing minute ventilation. The objective of our proposal is to demonstrate that administration of dexmedetomidine, after opioid exposure, prevents a fatal outcome. If efficacy is demonstrated in rodents, we intend to pursue efficacy studies in a non- anesthetized sheep model of fentanyl overdose. This model will allow us to establish the doses of dexmedetomidine needed to produce a beneficial effect without sedation. The effects of intravenous and intranasal dexmedetomidine will be examined. Our intention is to obtain, via 505(b)2 pathway, an FDA approval for non-sedative doses of dexmedetomidine as a treatment of opioid overdose.

PROJECT NARRATIVE Opioid-induced muscle rigidity decreases the ability of the respiratory system to generate breaths while producing a state of hypermetabolism. When associated with a central depression of the drive to breathe, opioid- induced muscle rigidity can lead to a lethal hypoxemia. Our proposal aims to demonstrate, in rodent and large mammal models, the efficacy of low-dose intravenous or intranasal dexmedetomidine – already FDA approved in humans for other indications – as a countermeasure against opioid overdose.