ABSTRACT
BACKGROUND: Although opioid receptor function in humans is clearly reduced during opioid dependence, what happens to the receptor in early abstinence is not understood. AIMS: This study sought to examine changes in opioid receptor availability in early abstinence from opioid dependence. METHOD: Ten people with opioid dependence who had completed in-patient detoxification and 20 healthy controls underwent [11C]-diprenorphine positron emission tomography. Clinical variables were assessed with structured questionnaires. Opioid receptor binding was characterised as the volume of distribution of [11C]-diprenorphine using a template of predefined brain volumes and an exploratory voxel-by-voxel analysis. RESULTS: Compared with controls, participants with opioid dependence had increased [11C]-diprenorphine binding in the whole brain and in 15 of the 21 a priori regions studied. CONCLUSIONS: This study suggests that opioid receptor binding is increased throughout the brain in early abstinence from dependent opioid use. These data complement the findings in cocaine and alcohol dependence.
Subject(s)
Brain/metabolism , Diprenorphine , Narcotic Antagonists , Opiate Alkaloids/metabolism , Opioid-Related Disorders/metabolism , Receptors, Opioid/metabolism , Adult , Brain/diagnostic imaging , Case-Control Studies , Diprenorphine/metabolism , Female , Humans , Male , Middle Aged , Narcotic Antagonists/metabolism , Opiate Alkaloids/pharmacology , Positron-Emission Tomography/methods , Substance Withdrawal Syndrome/metabolismABSTRACT
Substitute methadone prescribing is one of the main modes of treatment for opioid dependence with established evidence for improved health and social outcomes. However, the pharmacology underpinning the effects of methadone is little studied despite controversies about dosing in relation to outcome. We therefore examined the relationship between methadone dose and occupation of opioid receptors in brain using the positron emission tomography (PET) radioligand [(11)C]diprenorphine in humans and rats. Eight opioid-dependent subjects stable on their substitute methadone (18-90 mg daily) had an [(11)C]diprenorphine PET scan at predicted peak plasma levels of methadone. These were compared with eight healthy controls. No difference in [(11)C]diprenorphine binding was found between the groups, with no relationship between methadone dose and occupancy. Adult male Sprague-Dawley rats that had been given an acute i.v. injection of methadone hydrochloride (0.35, 0.5, 0.7, or 1.0 mg kg(-1)) before [(11)C]diprenorphine showed a dose-dependent increase in biodistribution but no reduction in [(11)C]diprenorphine binding. We suggest that the lack of a dose-dependent relationship between methadone dose, either given chronically in human or acutely in rat, and occupancy of opioid receptor measured with [(11)C]diprenorphine PET is related to efficacy of this opioid agonist at very low levels of opioid receptor occupancy. This has implications for understanding the actions of methadone in comparison with other opioid drugs such as partial agonists and antagonists.
Subject(s)
Diprenorphine/pharmacology , Methadone/pharmacology , Opioid-Related Disorders/metabolism , Receptors, Opioid/metabolism , Adult , Animals , Behavior, Addictive , Carbon Radioisotopes , Diprenorphine/chemistry , Humans , Male , Middle Aged , Rats , Rats, Sprague-Dawley , Time FactorsABSTRACT
We investigated the functional connectivity of brain regions activated during opiate craving. Previously we used recorded autobiographical scripts to induce opiate craving in 12 abstinent opiate-dependent subjects while they were undergoing positron emission tomography (PET) scanning using the regional cerebral blood flow (rCBF) tracer H2 15O. SPM99 was used to examine the connectivity patterns associated with the primary brain regions activated in response to drug-craving memories (anterior cingulate, AC) and correlated with opiate craving (orbitofrontal cortex, OFC). Two separate connectivity patterns were identified associated with the OFC and AC regions. The AC region was associated with activity in the left temporal region. The left OFC region activity correlated with activity in the right OFC, and left parietal and posterior insular regions. There was also a positive association with the hippocampus and brainstem. Both the AC and OFC regions showed a negative association with posterior visual areas. We suggest that the patterns of functional connectivity reflect the ability of drug-related stimuli to activate attentional and memory circuits to a greater degree than non-drug-related stimuli. This argues that neural circuits of dependence and craving are not specific "craving" or "addiction" brain regions but are "normal" circuits activated to a greater degree.
