Opioid Receptor Imaging with Positron Emission Tomography and [18F]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: The early developments of brain positron emission tomography (PET), including the methodological advances that have driven progress, are outlined. The considerable past achievements of brain PET have been summarized in collaboration with contributing experts in specific clinical applications including cerebrovascular disease, movement disorders, dementia, epilepsy, schizophrenia, addiction, depression and anxiety, brain tumors, drug development, and the normal healthy brain. Despite a history of improving methodology and considerable achievements, brain PET research activity is not growing and appears to have diminished. Assessments of the reasons for decline are presented and strategies proposed for reinvigorating brain PET research. Central to this is widening the access to advanced PET procedures through the introduction of lower cost cyclotron and radiochemistry technologies. The support and expertize of the existing major PET centers, and the recruitment of new biologists, bio-mathematicians and chemists to the field would be important for such a revival. New future applications need to be identified, the scope of targets imaged broadened, and the developed expertize exploited in other areas of medical research. Such reinvigoration of the field would enable PET to continue making significant contributions to advance the understanding of the normal and diseased brain and support the development of advanced treatments.Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 03/2012; 32(7):1426-54. DOI:10.1038/jcbfm.2012.20 · 5.34 Impact Factor
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ABSTRACT: Nearly 90 years of scientific research have led to the use of PET and the ability to forge advances in the field of oncology. In this Historial Review we outline the key developments made with this imaging technique, including the evolution of cyclotrons and scanners, together with the associated advances made in image reconstruction, presentation, analysis of data, and radiochemistry. The applications of PET to experimental medicine are summarised, and we cover how these are related to the use and development of PET, especially in the assessment of tumour biology and pharmacology. The use of PET in clinical oncology and for tissue pharmacokinetic and pharmacodynamic studies as a means of supporting drug development is detailed. The current limitations of the technology are also discussed.The Lancet Oncology 03/2012; 13(3):e116-25. DOI:10.1016/S1470-2045(11)70183-8 · 24.73 Impact Factor
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ABSTRACT: This chapter selectively discusses recent advances in human experimental models relating to the treatment of opioid dependence. I critically review three independent lines of research conducted during the past decade with heroin-dependent volunteers. One research strategy involves studying the µ-opioid receptor (µOR), which is the molecular target for the reinforcing and physical dependence producing effects of heroin-like drugs. This has been accomplished by varying medication dose conditions, measuring the availability of brain µ-receptors in vivo and plasma pharmacokinetics, then correlating these biological concentration measures with clinically relevant endpoints including opioid withdrawal symptoms, heroin craving, and blockade of the euphoric and respiratory depressant effects of µ-agonist challenges. These studies provide an initial benchmark for estimating µOR occupancy or plasma concentration requirements for effective pharmacotherapy. A second research strategy determines the conditions under which µ-agonist medications function as reinforcers, and the ability of medication dose and the availability of non-drug alternative reinforcement to attenuate opioid choice. Taken together, these studies provide information relevant to the ability of the medication to stimulate adherence and reduce drug demand. A third research strategy seeks to determine whether non-opioid medications can attenuate the naloxone-precipitated (i.e. withdrawal related) discriminative stimulus, subjective and/or physiological effects in opioid-maintained individuals. These studies aim to identify compounds that may be safe and effective adjuncts during opioid detoxification and, potentially, anti-relapse agents. Evidence is also reviewed concerning individual differences identified in these models. Implications of these findings for clinical treatment are also discussed.Trends in Substance Abuse Research, 01/2006: chapter Human experimental therapeutic models in opioid dependence: translational research advances and implications: pages 1-55; Nova Science Publishers, Inc.., ISBN: 1-60021-368-5