TY - JOUR T1 - Fentanyl but not Morphine Interacts with Non-Opioid Recombinant Human Neurotransmitter Receptors and Transporters JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.120.265561 SP - jpet.120.265561 AU - Randy Torralva AU - Amy J Eshleman AU - Tracy L Swanson AU - Jennifer L Schmachtenberg AU - William E Schutzer AU - Shelley H Bloom AU - Katherine M Wolfrum AU - John F Reed AU - Aaron Janowsky Y1 - 2020/01/01 UR - http://jpet.aspetjournals.org/content/early/2020/06/08/jpet.120.265561.abstract N2 - Synthetic opioids, including fentanyl and its analogues, have therapeutic efficacy in analgesia and anesthesia. However, their illicit use in the U.S. has increased, and contributed to the number one cause of death for adults 18-50 years old. Fentanyl and the heroin metabolite, morphine, induce respiratory depression that can be treated with the mu opioid receptor (MOR) antagonist, naloxone. With higher or more rapid dosing, fentanyl, more than morphine, causes chest wall rigidity, and can also induce rapid onset laryngospasm. Because non-MORs could mediate differing clinical manifestations, we examined the interactions of fentanyl and morphine at recombinant human neurotransmitter transporters, G protein-coupled receptors, and the NMDA glutamate receptor. Both drugs were agonists at MOR, kappa, and delta opioid receptors. Morphine had little or no affinity at other human receptors and transporters (Ki or IC50 value >100μM). However, fentanyl had Ki values of 1,407nM and 1,100nM at α1A and α1B adrenoceptor subtypes, respectively, Ki values of 1,049nM and 1,670nM at dopamine D4.4 and D1 receptor subtypes, respectively, and also blocked [3H]neurotransmitter uptake by the vesicular monoamine transporter 2 (VMAT2) (IC50 = 911nM). Pharmacokinetic models indicate that these Ki and IC50 values are pharmacologically relevant. Fentanyl had little affinity for other receptors or transporters. Thus, noradrenergic disposition at specific receptor subtypes in relevant organs may play a role in respiratory and cardiothoracic effects of fentanyl. Data suggest that less selective fentanyl receptor pharmacology could play a role in the different clinical effects of morphine compared to fentanyl, including fentanyl-induced deaths following illicit use.SIGNIFICANCE STATEMENT The synthetic opioid, fentanyl, induces different clinical effects including rapid onset muscular rigidity, vocal cord closure and rapid death, than the heroin metabolite, morphine. Our data indicate for the first time that the two drugs have very different effects at recombinant human neurotransmitter receptors and transporters that might explain those clinical differences. ER -