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.
SourceAvailable from: Darren Robert Quelch[Show abstract] [Hide abstract]
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; DOI:10.1038/jcbfm.2014.117 · 5.34 Impact Factor
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ABSTRACT: Methadone maintenance treatment (MMT) is safe and effective for heroin addiction, but the neural basis of the length effects of long-term MMT on brain activity during craving in former heroin addicts is unclear. This study explored it by comparing the brain activations of heroin addicts with different length of MMT during pictorial presentation of heroin-related cue. Fifteen male former heroin addicts successfully treated by MMT less than 1 year (Group A), 15 matched patients with 2-3 year MMT (Group B) and 17 healthy controls underwent functional magnetic resonance imaging while heroin-related and neutral stimuli were present to them. Subjective cue-elicited craving was measured with visual analog scale before and after imaging. Then, partial correlation analysis to reveal the relationship between drug-related blood oxygen level dependent (BOLD) signal intensity and heroin or methadone use history. Finally, self-reported craving was not different between Group A and B before and after scanning. Compared with Group A, Group B had a significant reduced brain activity to heroin-related minus neural cues in the bilateral caudate. After controlling for the variable heroin use history, the drug-related BOLD signal intensity in the bilateral caudate was negatively correlated with MMT duration and total methadone consumption. When MMT history was controlled, the drug-related activity intensity in right caudate had a positive correlation with heroin daily dosage. Long-term MMT may improve heroin-craving response by modulating the impaired function in the bilateral dorsal striatum caused by former heroin use.Neuroscience Letters 08/2014; 581. DOI:10.1016/j.neulet.2014.08.026 · 2.06 Impact Factor
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ABSTRACT: Drug addiction is a chronic relapsing disease. Most users will relapse back to using drugs over and over again throughout their life. These relapses may become more frequent in the presence of contextual reminders. We aimed to examine associations between the ability to maintain a medication-free life-style and the capability to learn and reverse positive and negative stimulus-outcome associations in the presence of neutral and drug-related contextual reminders.Drug and Alcohol Dependence 09/2014; DOI:10.1016/j.drugalcdep.2014.08.016 · 3.28 Impact Factor