Airway compromise and skeletal muscle rigidity as toxicity contributors in synthetic opioid and methamphetamine co-administered rats

The United States is battling a drug overdose crisis fueled by deaths from the synthetic opioid fentanyl and from the neurostimulant methamphetamine. A better understanding of the toxicity caused by these drugs, alone and in combination, will guide strategies to prevent and to medically manage victims of these drugs. Opioids cause death through respiratory depression and methamphetamine through the consequences of adrenergic excess. Opioids, and potent synthetic opioids in particular, cause skeletal muscle rigidity and airway compromise/glottic closure (GC). The relative contributions of synthetic opioid-induced GC to overall respiratory depression are unknown. Additionally, it is unknown whether skeletal muscle rigidity and GC occur through similar mechanisms and, as such, would be amenable to similar therapies. Therefore, in Aim 1, we will test in rats the hypothesis that respiratory depression observed with fentanyl and its higher potency analog, sufentanil, is due in part to GC, and that GC is a function of opioid onset rate. We will also test the hypothesis that drugs that prevent/reverse opioid-induced skeletal muscle rigidity (e.g., dexmedetomidine) will also prevent/reverse GC. In preliminary studies, we determined that simultaneous administration of d- methamphetamine with sufentanil was, unexpectedly, lethal in rats likely through the induction of pulmonary edema; fentanyl was better tolerated, and morphine even more so. Therefore, in Aim 2, we will test the hypothesis that synthetic opioid-induced GC is worsened by d-methamphetamine and poorly tolerated; d- methamphetamine is a metabolic and breathing stimulant, and a closed airway may precipitate negative pressure pulmonary edema.