Naloxone’s displacement of [11C]carfentanil and duration of receptor occupancy in the rat brain: implications for opioid overdose reversal

Abstract

The continuous rise in opioid overdoses in the United States is predominantly driven by very potent synthetic opioids, mostly fentanyl and its derivatives (fentanyls). Although naloxone (NLX) has been shown to effectively reverse overdoses by conventional opioids, there may be a need for higher or repeated doses of NLX to revert overdoses from highly potent fentanyls. Here, we used positron emission tomography (PET) to assess NLX’s dose-dependence on both its rate of displacement of [11C]carfentanil ([11C]CFN) binding and its duration of mu opioid receptor (MOR) occupancy in the male rat brain. We showed that clinically relevant doses of intravenously (IV) administered NLX (0.035mg/kg, Human Equivalent Dose(HED) 0.4mg; 0.17mg/kg, HED 2mg) rapidly displaced the specific binding of [11C]CFN in thalamus in a dose-dependent manner. Brain MOR occupancy by IV NLX was greater than 90% at 5 minutes after NLX administration for both doses, but only 50% occupancy remained at 27.3 min and at 85 min after 0.035mg/Kg and 0.17 mg/Kg NLX, respectively. This indicates that the duration of NLX occupancy at MORs is short-lived. Overall, these results show that clinically relevant doses of IV NLX can promptly displace fentanyls at brain MORs, but that repeated or higher NLX doses may be required to prevent re-narcotization following overdoses with long-acting fentanyls.

Brain oxygen responses induced by opioids: focus on heroin, fentanyl, and their adulterants

“…We first examined the effects of naloxone delivered subcutaneously at a relatively small, clinically relevant dose (0.2 mg/kg or 14 mg/70 kg) on brain oxygen responses induced by iv heroin (0.1 mg/kg) (92). At this dose, naloxone induces robust blockade of mu-opioid receptors (93). In our experiment, pre-treatment with naloxone fully blocked the biphasic effect of heroin (Figure 9A).…”

Xylazine suppresses fentanyl consumption during self-administration and induces a unique sex-specific withdrawal syndrome that is not altered by naloxone in rats.

“…Fentanyl is associated with a profound increase in fatal overdose cases (Wilson et al, 2020). Naloxone (Narcan) is a MOR antagonist used clinically to reverse fentanyl's occupancy of brain MORs (Kang et al, 2022), reversing opioid overdose and precipitating opioid withdrawal (Kosten & Baxter, 2019;Rzasa Lynn & Galinkin, 2018). Recently, xylazine, an adrenergic α 2a receptor (A2aR) agonist sold as a veterinary anesthetic, has been increasingly detected in more fentanyl-positive urine screens and fentanyl overdose deaths (Nunez et al, 2021).…”

Evaluating the rate of reversal of fentanyl-induced respiratory depression using a novel long-acting naloxone nanoparticle, cNLX-NP

“…Naloxone is rapidly eliminated and has a relatively short half-life of between 30 -120 min (21)(22)(23). A recent study showed that naloxone occupancy of MORs decreased from 90% occupancy 5 min after administration to 50% occupancy 20 min later, which demonstrated how short-lived naloxone's effects may be (24). Nalmefene, which is structurally similar to naloxone, has a much longer elimination half-life of approximately 11 hr in humans (25).…”