Biomedical subjects

Mark R C Daglish

Publications and source records attributed to Mark R C Daglish.

3 recordsLinked to original sources

PubMed2004

Using [11C]diprenorphine to image opioid receptor occupancy by methadone in opioid addiction: clinical and preclinical studies.

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.

Adult↗

PubMed2003

Brain imaging studies in human addicts.

Addiction provides fertile ground for the application of the tools of functional neuroimaging. They can be divided into studies of neural activity and neurotransmitter function. Using the former, both opiates and stimulants cause a global decrease in brain metabolism. Against this background, acute doses have still been shown to produce relative increases in brain activation in specific regions, e.g., anterior cingulate, thalamus, and amygdala. These are also regions frequently found with cue-exposure paradigms. Our own work on cue-exposure has shown that heroin-related stimuli provoke activation of the anterior cingulate and orbitofrontal regions. Brain metabolism has also been shown to increase in drug withdrawal from alcohol and cocaine. Neurotransmitter studies have shown that in alcohol dependence, GABA(A)-benzodiazepine (GABA-BDZ) receptors are reduced in a number of brain regions and suggest that there may be 'capacity within the system' in some benzodiazepine functions, but tolerance to others, e.g., time asleep. Finally, 11C-Ro15-4513 offers new opportunities for imaging the GABA-BDZ system.

Brain↗

PubMed2003

Functional connectivity analysis of the neural circuits of opiate craving: "more" rather than "different"?

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.

Brain Stem↗