In humans, metyrapone blocks the final step of cortisol synthesis, that is, 11-α-hydroxylation. In the single oral dose test using metyrapone, the synthesis of cortisol is blocked for about 8 hours, and then returns to normal. Therefore, one can measure the levels

of ACTH (which also reflect the equimolar release and levels of beta-endorphin) following metyrapone administration which are elevated because with Cortisol synthesis blocked, and the normal negative feedback is transiently cut off. In healthy human beings, with normal endogenous opioid systems, the mu-opioid receptor Inhibitors,research,lifescience,medical system responds to bring a check, or brake, to the increased release and levels of ACTH (and beta-endorphin). However, we had shown in several earlier studies that in medication-free, drug-free former heroin addicts, there is no such mu-opio!d receptor-mediated

brake, and thus hyper-responsivity to metyrapone testing is observed (reviewed in refs 5,7). Further, Inhibitors,research,lifescience,medical we had reported that in abstinent cocaine addicts a similar hyper-responsivity to metyrapone testing exists.50 This hyper-responsivity, therefore, suggests a relative endorphin deficiency, which our laboratory -based studies also support.30-33,50 As discussed Inhibitors,research,lifescience,medical above, we have found that chronic binge cocaine administration causes an increase in gene expression in the mu-opioid receptor, as well as an increase in density in mu-opioid receptors, in specific brain regions with abundant dopaminergic terminals, and, further, in recent studies, we have found that this increase in mu-opioid receptor density persists for a protracted period of time after last cocaine Inhibitors,research,lifescience,medical exposure.30,32-35 However, we have also shown that there is no increase of the endogenous opioids that bind at the mu receptor. Thus a relative endorphin deficiency develops (or possibly was present a priori on a genetic or environmentally-induced basis). Subsequently,

Frost and colleagues, using positron emission tomography Inhibitors,research,lifescience,medical (PET) showed similarly the mu-opioid receptor density being increased in recently-abstinent cocaine addicts, and further more recently have shown that this increase persists for protracted periods of time into successful check cocaine abstinence.55,56 Thus, a relative endorphin deficiency has been documented both in ROCK inhibitor humans as well as in rodent models, in humans directly shown by testing of the stress-responsive system. In several studies, we have found that metyrapone responsivity is abnormal in opiate addicts, but becomes normalized in methadone maintenance patients (reviewed in refs 5,7). We also have shown that abnormal hyper-responsivity occurs in cocaine addicts.5,7 In a more recent study, we again documented the normalization during methadone maintenance treatment.