Opioid receptor imaging with positron emission tomography and [(18)F]cyclofoxy in long-term, methadone-treated former heroin addicts.
ABSTRACT Stabilized methadone-maintained former heroin addicts (MTPs) treated with effective doses of methadone have markedly reduced drug craving; reduction or elimination of heroin use; normalized stress-responsive hypothalamic-pituitary-adrenal, reproductive, and gastrointestinal function; and marked improvement in immune function and normal responses to pain, all of which are physiological indices modulated in part by endogenous and exogenous opioids directed at the mu and, in some cases, the kappa-opioid systems. This study was performed to explore opioid receptor binding in MTPs. Fourteen normal, healthy volunteers and 14 long-term MTPs in treatment for 2 to 27 years and receiving 30 to 90 mg/day of methadone were studied with positron emission tomography using tracer amounts of [(18)F]cyclofoxy, an opioid antagonist that labels mu and kappa opioid receptors. Imaging was performed in the morning, 22 h after the last dose of methadone in patients, and concurrent plasma levels of methadone were determined. Five brain regions of specific interest for addiction and pain research (thalamus, amygdala, caudate, anterior cingulate cortex, and putamen) were among the six regions of highest [(18)F]cyclofoxy binding. Specific binding of [(18)F]cyclofoxy was lower by 19 to 32% in these regions in MTPs compared with those in normal volunteers. The degree to which specific binding was lower in caudate and putamen correlated with methadone plasma levels (P <.01 and P <.05, respectively), suggesting that these lower levels of binding may be related to receptor occupancy with methadone and that significant numbers of opioid receptors may be available to function in their normal physiological roles.
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ABSTRACT: Introduction: Methadone and buprenorphine are maintenance replacement therapies for opioid dependence; they are also used for pain management. Methadone and buprenorphine (to a lesser extent) have seen sharp increases in mortality associated with their use. They have distinct routes of metabolism (mostly cytochrome P450 dependent), and distinct pharmacologic activity of metabolites. As such, metabolism may play a role in differences in their toxicity. Areas covered: This article reviews peer-reviewed literature obtained from PubMed searches and literature referenced within. The review considers first an overview of drug use and mortality over the past decade. It then provides extensive detail on the in vitro and in vivo human metabolism of methadone and buprenorphine. Using both human and experimental animal studies it then presents the pharmacodynamic activity of parent drug and metabolites at the mu-opioid receptor, as P-glycoprotein substrates and plasma/brain concentration ratios, and activity at the hERG K(+) channel. Lessons learned from drug interaction studies in humans are then examined in an attempt to bring together the combined information. Expert opinion: The use and misuse of these drugs contributes to the epidemic in opioid-associated mortalities. A better understanding of metabolism-, transport- and co-medication-induced changes will contribute to their safer use.Expert Opinion on Drug Metabolism & Toxicology 03/2013; · 2.94 Impact Factor
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ABSTRACT: Understanding the cellular processes underpinning the changes in binding observed during positron emission tomography neurotransmitter release studies may aid translation of these methodologies to other neurotransmitter systems. We compared the sensitivities of opioid receptor radioligands, carfentanil, and diprenorphine, to amphetamine-induced endogenous opioid peptide (EOP) release and methadone administration in the rat. We also investigated whether agonist-induced internalization was involved in reductions in observed binding using subcellular fractionation and confocal microscopy. After radioligand administration, significant reductions in [(11)C]carfentanil, but not [(3)H]diprenorphine, uptake were observed after methadone and amphetamine pretreatment. Subcellular fractionation and in vitro radioligand binding studies showed that amphetamine pretreatment only decreased total [(11)C]carfentanil binding. In vitro saturation binding studies conducted in buffers representative of the internalization pathway suggested that μ-receptors are significantly less able to bind the radioligands in endosomal compared with extracellular compartments. Finally, a significant increase in μ-receptor-early endosome co-localization in the hypothalamus was observed after amphetamine and methadone treatment using double-labeling confocal microscopy, with no changes in δ- or κ-receptor co-localization. These data indicate carfentanil may be superior to diprenorphine when imaging EOP release in vivo, and that alterations in the ability to bind internalized receptors may be a predictor of ligand sensitivity to endogenous neurotransmitter release.Journal of Cerebral Blood Flow & Metabolism advance online publication, 9 July 2014; doi:10.1038/jcbfm.2014.117.Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 07/2014; · 5.46 Impact Factor
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ABSTRACT: Heroin, with low affinity for μ-opioid receptors, has been considered to act as a prodrug. In order to study the pharmacokinetics of heroin and its active metabolites after intravenous (i.v.) administration, we gave a bolus injection of heroin to rats and measured the concentration of heroin and its metabolites in blood and brain extracellular fluid (ECF). After an i.v. bolus injection of heroin to freely moving Sprague-Dawley rats, the concentrations of heroin and metabolites in blood samples from the vena jugularis and in microdialysis samples from striatal brain ECF were measured by ultraperformance liquid chromatography-tandem mass spectrometry. Heroin levels decreased very fast, both in blood and brain ECF, and could not be detected after 18 and 10 minutes respectively. 6-MAM increased very rapidly, reaching its maximal concentrations after 2.0 and 4.3 minutes respectively and falling thereafter. Morphine increased very slowly, reaching its maximal levels, which were 6 times lower than the highest 6-MAM concentrations, after 12.6 and 21.3 minutes, with a very slow decline during the rest of the experiment and only surpassing 6-MAM levels at least 30 minutes after injection. After an i.v. heroin injection, 6-MAM was the predominant opioid present shortly after injection and during the first 30 minutes, not only in the blood but also in rat brain ECF. 6-MAM might therefore mediate most of the effects observed shortly after heroin intake, and this finding questions the general assumption that morphine is the main and most important metabolite of heroin.British Journal of Pharmacology 07/2013; · 5.07 Impact Factor