Fentanyl but not Morphine Interacts with Nonopioid Recombinant Human Neurotransmitter Receptors and Transporters

Abstract

Synthetic opioids, including fentanyl and its analogs, have therapeutic efficacy in analgesia and anesthesia. However, their illicit use in the United States 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 m 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 N-methyl-Daspartate glutamate receptor. Both drugs were agonists at MOR, k, and d opioid receptors. Morphine had little or no affinity at other human receptors and transporters (K i or IC 50 value .100 mM). However, fentanyl had K i values of 1407 and 1100 nM at a 1A and a 1B adrenoceptor subtypes, respectively, and K i values of 1049 and 1670 nM at dopamine D4.4 and D1 receptor subtypes, respectively; it also blocked [ 3 H]neurotransmitter uptake by the vesicular monoamine transporter 2 (IC 50 = 911 nM). Pharmacokinetic models indicate that these Ki and IC 50 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 with fentanyl, including fentanyl-induced deaths after illicit use. SIGNIFICANCE STATEMENTThe 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.

Tempol Reverses the Negative Effects of Morphine on Arterial Blood-Gas Chemistry and Tissue Oxygen Saturation in Freely-Moving Rats

“…The clinical uses for fentanyl and morphine overlap, but there are many instances where one is preferred over the other ( Dahan et al, 2010 ; 2018 ; Boom et al, 2012 ). Moreover, there are substantial similarities, but also equally substantial differences, in the abilities of fentanyl and morphine to affect cardiorespiratory parameters in humans and animals ( Dahan et al, 2010 ; 2018 ; Boom et al, 2012 ; Henderson et al, 2014 ; Torralva and Janowsky, 2019 ) for reasons including, differential actions of the parent opioids and their metabolites on non-opioid receptors ( Torralva et al, 2020 ). Questions arising from our first report on Tempol ( Baby et al, 2021 ) ask 1) whether the presence of isoflurane anesthesia is a factor in the ability of Tempol to blunt the negative cardiorespiratory effects of fentanyl; 2) whether Tempol uniquely affects fentanyl or is active against other opioids; and 3) whether the efficacy of Tempol is related to it being a pretreatment.…”

Molecular Mechanisms of Action of Novel Psychoactive Substances (NPS). A New Threat for Young Drug Users with Forensic-Toxicological Implications

“…Synthetic cannabinoids, also called “Spice,” are synthetic cannabinoid receptor agonists (SCRAs) which have been originally developed for their potential therapeutic role by exploiting the endocannabinoid system [ 38 , 39 , 40 ]. Since then, “Spice” products have been sold as legal marijuana surrogate, becoming very popular among younger people and now representing the widest class of NPS.…”

Pharmacological Profiling of Antifentanyl Monoclonal Antibodies in Combination with Naloxone in Pre- and Postexposure Models of Fentanyl Toxicity

“…While the mechanisms underlying WCS are not entirely understood, it appears that WCS is primarily mediated by alpha-adrenergic and cholinergic signaling rather than opioid receptor signaling (Torralva and Janowsky, 2019). In contrast to morphine and other opioids, fentanyl has demonstrated interaction with non-opioid receptors including adrenoceptors (Torralva et al, 2020). Hence, NLX or other opioid receptor-specific pharmacotherapy is not effective in reversing WCS (Miner et al, 2021).…”