Naloxone's dose-dependent displacement of [11C]carfentanil and duration of receptor occupancy in the rat brain

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 (0.035 mg/kg, Human Equivalent Dose (HED) 0.4 mg; 0.17 mg/kg, HED 2 mg) rapidly displaced the specific binding of [¹¹C]CFN in the thalamus in a dose-dependent manner. Brain MOR occupancy by IV NLX was greater than 90% at 5 min after NLX administration for both doses, but at 27.3 min after 0.035 mg/kg dose and at 85 min after 0.17 mg/kg NLX, only 50% occupancy remained. 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 repeated or higher NLX doses may be required to prevent re-narcotization following overdoses with long-acting fentanyls.

Figure 1

Structures of fentanyls and naloxone. Each circle represents positions which have been abundantly reported to generate illegal fentanyls via chemical modification with various substituents.

Figure 2

[¹¹C]CFN displacement study with two doses of IV NLX (baseline, n = 3; 0.035 mg/kg, n = 3; 0.17 mg/kg, n = 3). Averaged time-activity curves in the cerebellum (A) and thalamus (B) were generated in standard uptake value (SUV, g/mL). Averaged SUVs of thalamus to cerebellum ratios (SUVr) for baseline and the two NLX doses (C). Dose-dependent displacement rate was expressed as gradient change after NLX post-treatment (D). NLX was administered at 15 min after [¹¹C]CFN injection.

Figure 3

Averaged PET brain images of [¹¹C]CFN for baseline and the NLX treatments (0.035 mg/kg and 0.17 mg/kg NLX) aligned with W. Schiffer Rat Brain atlas using PMOD. NLX was given 15 min after [¹¹C]CFN administration to assess displacement. The top row corresponds to the average images obtained at 0–15 min and the bottom row corresponds to averaged images obtained at 15–30 min, in which at 15 min, NLX was injected at 0.035 and 0.17 mg/kg doses.

Figure 4

MOR occupancy profiles after IV NLX for two doses (circle, 0.035 mg/kg; rectangle, 0.17 mg/kg). Occupancy data averaged for each time point were plotted with a sigmoidal function. NLX 0.035 mg/kg corresponds to 0.4 mg HED and NLX 0.17 mg/kg to 2 mg HED. Error bars correspond to standard deviations.

Figure 5

Averaged plasma concentration after IV NLX in rats. NLX was administered intravenously for each of the two doses (0.035 mg/kg, n = 3; 0.17 mg/kg, n = 3).