Naloxone’s dose-dependent displacement of [11C]carfentanil and duration of receptor occupancy in the rat brain (original) (raw)
Related papers
2022
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 8...
European Journal of Nuclear Medicine and Molecular Imaging, 2009
Purpose [ 11 C]Carfentanil has been widely used in positron emission tomography (PET) studies for measuring µ-opioid receptor binding in humans, but the reproducibility of the binding parameter estimates is unknown. Materials and methods Eight healthy volunteers were scanned twice during the same day with [ 11 C]carfentanil PET, and binding to receptors was assessed with both reference tissue and arterial plasma input-based models using region of interest (ROI) and voxel-based quantification.
Molecules
Naloxone (NLX) is a mu receptor antagonist used to treat acute opioid overdoses. Currently approved doses of naloxone to treat opioid overdoses are 4 mg intranasal (IN) and 2 mg intramuscular (IM). However, higher mu receptor occupancy (RO) may be required to treat overdoses due to more potent synthetic opioids such as fentanyl and carfentanil that have entered the illicit drug market recently. To address this need, a higher dose of NLX has been investigated in a 5 mg IM formulation called ZIMHI but, while the effects of intravenous (IV) and IN administration of NLX on the opioid mu receptor occupancy (RO) have been studied, comparatively little is known about RO for IM administration of NLX. The goal of this study was to examine the effect of IM dosing of NLX on mu RO in rhesus macaques using [11C]carfentanil positron emission tomography (PET) imaging. The lowest dose of NLX (0.06 mg/kg) approximated 51% RO. Higher doses of NLX (0.14 mg/kg, 0.28 mg/kg) resulted in higher mu RO of 7...
Imaging of opioid receptors in the central nervous system
Brain, 2007
In vivo functional imaging by means of positron emission tomography (PET) is the sole method for providing a quantitative measurement of k-, i and d-opioid receptor-mediated signalling in the central nervous system. During the last two decades, measurements of changes to the regional brain opioidergic neuronal activationç mediated by endogenously produced opioid peptides, or exogenously administered opioid drugsçhave been conducted in numerous chronic pain conditions, in epilepsy, as well as by stimulant-and opioidergic drugs. Although several PET-tracers have been used clinically for depiction and quantification of the opioid receptors changes, the underlying mechanisms for regulation of changes to the availability of opioid receptors are still unclear. After a presentation of the general signalling mechanisms of the opioid receptor system relevant for PET, a critical survey of the pharmacological properties of some currently available PET-tracers is presented. Clinical studies performed with different PET ligands are also reviewed and the compound-dependent findings are summarized. An outlook is given concluding with the tailoring of tracer properties, in order to facilitate for a selective addressment of dynamic changes to the availability of a single subclass, in combination with an optimization of the quantification framework are essentials for further progress in the field of in vivo opioid receptor imaging.
Intranasal naloxone rapidly occupies brain mu-opioid receptors in human subjects
Neuropsychopharmacology, 2019
Nasal spray formulations of naloxone, a mu-opioid receptor (MOR) antagonist, are currently used for the treatment of opioid overdose. They may have additional therapeutic utility also in the absence of opioid agonist drugs, but the onset and duration of action at brain MORs have been inadequately characterized to allow such projections. This study provides initial characterization of brain MOR availability at high temporal resolution following intranasal (IN) naloxone administration to healthy volunteers in the absence of a competing opioid agonist. Fourteen participants were scanned twice using positron emission tomography (PET) and [ 11 C]carfentanil, a selective MOR agonist radioligand. Concentrations of naloxone in plasma and MOR availability (relative to placebo) were monitored from 0 to 60 min and at 300-360 min post naloxone. Naloxone plasma concentrations peaked at~20 min post naloxone, associated with slightly delayed development of brain MOR occupancy (half of peak occupancy reached at~10 min). Estimated peak occupancies were 67 and 85% following 2 and 4 mg IN doses, respectively. The estimated half-life of occupancy disappearance was~100 min. The rapid onset of brain MOR occupancy by IN naloxone, evidenced by the rapid onset of its action in opioid overdose victims, was directly documented in humans for the first time. The employed high temporal-resolution PET method establishes a model that can be used to predict brain MOR occupancy from plasma naloxone concentrations. IN naloxone may have therapeutic utility in various addictions where brain opioid receptors are implicated, such as gambling disorder and alcohol use disorder.
ACS Omega
Overdose is the main cause of mortality among heroin users. Many of these overdose-induced deaths can be prevented through the timely administration of naloxone (NLX), a nonselective mu (μ)-, kappa (κ)-, and delta (δ)-opioid receptor antagonist. NLX competitively inhibits opioid-overdose-induced respiratory depression without eliciting any narcotic effect itself. The aim of this study was to investigate the antagonistic action of NLX by comparing its distribution to that of 6-monacetylmorphine (6-MAM), heroin's major metabolite, in a rodent model using mass spectrometric imaging (MSI) in combination with liquid chromatography−tandem mass spectrometry (LC−MS/MS). Male Sprague−Dawley rats (n = 5) received heroin (10 mg kg −1) intraperitoneally, NLX (10 mg kg −1) intranasally, and NLX injected intranasally 5 min after heroin administration. The animals were sacrificed 15 min after dose and brain tissues were harvested. The MSI image analysis showed a region-specific distribution of 6-MAM in the brain regions including the corpus callosum, hippocampal formation, cerebral cortex, corticospinal tracts, caudate putamen, thalamus, globus pallidus, hypothalamus, and basal forebrain regions of the brain. The antagonist had a similar biodistribution throughout the brain in both groups of animals that received NLX or NLX after heroin administration. The MSI analysis demonstrated that the intensity of 6-MAM in these brain regions was reduced following NLX treatment. The decrease in 6-MAM intensity was caused by its displacement by the antagonist and its binding to these receptors in these specific brain regions, consequently enhancing the opioid elimination. These findings will contribute to the evaluation of other narcotic antagonists that might be considered for use in the treatment of drug overdose via MSI.
Imaging Human Brain Opioid Receptors: Applications to Substance Use Disorders
Opiate Receptors and Antagonists, 2009
Three types of opioid receptors (ORs: mu [µ], kappa [κ], and delta [δ]) are differentially distributed throughout the brain. Historically, the µOR has been of greatest clinical interest because it mediates therapeutic effects (e.g., analgesia and cough suppression) and nontherapeutic effects (e.g., abuse and physical dependence) of opioid agonists. This "dual-edged sword" underlies the classical dilemma of balancing safety and efficacy when µOR agonists are administered systemically to human subjects. Preclinical studies suggest that κORand δOR-specific agonists and antagonists could be useful in treating human substance use disorders, but the lack of such Food and Drug Administration (FDA)-approved medications significantly limits our understanding of the role of these molecular targets in the clinical setting. However, the µOR-specific radiotracer [ 11 C]-carfentanil has been used with positron emission tomography (PET) to elucidate the function of this endogenous system as it relates to substance use disorders, both with antagonists (e.g., naltrexone) and agonists (e.g., buprenorphine). The δOR-specific tracer [ 11 C]-methyl-naltrindole is also available for human use, but has not yet been applied to substance use disorders, and a κORspecific tracer has shown promise in preclinical testing. Advances in neuroscience and medication development are likely to yield significant progress that will improve our understanding of these disorders and clinical outcomes in the near future.
Imaging of ? opioid receptors in human brain by N1?- ([11C]methyl)naltrindole and PET
Synapse, 1996
Recently, we have developed the positron emitting radiotracer N1'-(["C]methyl)naltrindole (["ClMeNTI) and demonstrated its high selectivity for 6 opioid receptors in the mouse brain [Lever et al. (1992) Eur. J. Pharmacol., 216:449-4501. In the present study, we examined the selectivity of [WIMeNTI for the 6 opioid receptor in the human brain, using positron emission tomography (PET). The regional kinetics and distribution as we11 as the pharmacology confirmed the selectivity of [llC]MeNTI for 6 opioid receptor in the human brain. First, the regional kinetics of ["CIMeNTI are in accordance with the density of the 6 opioid receptor. Rapid washout in receptor-poor areas and prolonged retention in receptor-rich areas were observed. Second, the regional distribution of ["CIMeNTI correlated well (r = 0.91) with the in vitro distribution of 6 opioid sites but not with p or K site densities (r I 0.008 or r 5 0.014, respectively).