Rationale: Fentanyl remains the primary cause of fatal overdoses, and its co-use with methamphetamine (METH) is a growing concern. The optical isomers of METH, dextromethamphetamine (d-METH) and levomethamphetamine (l-METH), differ substantially in dose expression and thus may differentially contribute to the racemate’s bidirectional effects. Furthermore, it is unknown which of METH’s monoamine (MA) receptor mechanisms mediate these respiratory effects. Thus, systematic evaluation of monoamine receptor selective agents may identify treatment targets for OIRD. Methods: The two optical isomers of METH, d-METH and l-METH, were tested in adult male mice to determine their effects on basal and fentanyl-depressed minute volume (MVb; i.e., respiratory frequency x tidal volum) using whole-body plethysmography. Next, six selective agonists at MA receptors involved in METH’s activity [phenylephrine (PNE; α1), clonidine (CLON; α2), SKF-82958 (SKF; D1), quinpirole (QPR; D2), 8-OH-DPAT (8-OH; 5HT1A), and DOI (5HT2)] were singly tested on basal MVb, and then in combination with fentanyl. Results: d-METH elevated MVb and l-METH decreased MVb. Under fentanyl-depressed conditions, the bidirectional effects of racemic METH were recreated by d-METH while l-METH significantly exacerbated OIRD at 1.0 and 3.0 mg/kg. MVb was dose-dependently increased by PNE and SKF and decreased by CLON and QPR. Neither 8-OH nor DOI altered basal MVb. Under fentanyl-depressed conditions, SKF transiently elevated MVb, while PNE more persistently increased it, while DOI transiently increased MVb, and 8-OH decreased MVb. Conclusions: d-METH and l-METH differentially contribute to the bidirectional respiratory modulation observed with the racemate and selective activation of MA receptors altered basal respiration and OIRD.

Background and Purpose: The opioid epidemic remains one of the most pressing public health crises facing the United States. Rising rates of opioid-involved overdose deaths are presently driven primarily by fentanyl and related synthetic opioid agonists that are resistant to reversal by naloxone and increasingly used as adulterants or clandestine substitutes in illicitly produced opioids, sedatives, and psychostimulants. Deaths involving opioids typically result from lethal respiratory depression and it is currently unknown whether co-use of psychostimulants with opioids affects respiratory toxicity. Considering psychostimulant overdoses have increased over 3-fold since 2013, and half of those co-involved opioids, this is a cardinal question. Experimental Approach: Naloxone, d-amphetamine (AMPH), and (+/-)-methamphetamine (METH), were evaluated for their effects on basal and fentanyl-depressed respiration. Minute volume (MVb) was measured in awake, freely moving mice via whole-body plethysmography to quantify fentanyl-induced respiratory depression and its modulation by dose ranges of each test drug. Key Results: Naloxone reversed respiratory depression induced by fentanyl only at the highest dose tested (10 mg•kg-1). Both AMPH and METH exhibited bidirectional effects on MVb under basal conditions, producing depressions then elevations of respiration as dose increased. Under depressed conditions the bidirectional effects of AMPH and METH on respiration were exaggerated, exacerbating and then reversing fentanyl-induced depression as dose increased. Conclusions and Implications: These results indicate that co-use of amphetamines with fentanyl may worsen respiratory depression, but conversely, monoaminergic components of the amphetamines may possibly be exploited to mitigate fentanyl overdose.