Table 1.
The studies on PET-imaging of ORs in the CNS
| Study | Aim | Ligand | Modelling/statistical analysis/group size | Main findings | Interpretation/comments |
|---|---|---|---|---|---|
| Neurochemical mapping | |||||
| Jones et al., 1991 | Study of OR-binding in relation to the lateral and medial pain system. | [11C]DPN (μ-, κ- and δ- antagonist) | Ratio method, BPND/VOI/n = 2 | High OR binding in medial pain system and low OR binding in lateral pain system (SM1). | The medial pain system is likely to be more susceptible to exogenous and endogenous opioid neuromodulation than the so-called lateral pain system. |
| Baumgartner et al., 2006 | Study of OR-binding in relation to the lateral and medial pain system, focus on secondary sensory cortex. | [18F]FDPN (μ-, κ- and δ- antagonist) | Non-invasive Logan plot, BPND/VOI/n = 11 | All structures of the operculo-insular region (anterior and posterior insula, and parietal and frontal operculum) have high OR binding. Factor analysis revealed high loadings on operculo-insular region, ACC and putamen. | The operculo-insular region as part of the lateral pain system is influenced by opioids and displays a functional unit together with ACC and putamen. |
| Vogt et al., 1995 | Detailed analysis of OR binding in cingulate and adjacent cortex. | [11C]DPN (μ-, κ- and δ- antagonist) | Invasive compartment model, VT /VOI/n = 3 | Highest OR binding in ACC, rostral cingulofrontal transition and frontal cortices. There was a gradient from low to high binding to caudal ACC, PCC and superior frontal cortices. | Variations in binding may reflect functional specializations such as low binding in visuospatial areas and high binding in areas processing affective content. |
| Schadrack et al., 1999 | In vivo and in vitro studies of cerebellum OR binding and mRNA. Comparison of rat and human. | [11C]DPN (μ-, κ- and δ- antagonist) | Invasive SA, IRF60/VOI/n = 10 | No OR in rat cerebellum, and low to medium OR binding in human cerebellum. In human brain, there is a differential OR level in cerebellar cortex, vermis and dentate nuclei, and absence of δ-OR. mRNA mainly observed in granule cells and OR predominantly in the molecular layer. | Presence of opioidergic mechanisms in the human cerebellum in contrast to the rat. |
| Smith et al., 1998 | Regulation of μ-OR during the menstrual cycle. | [11C]CAF (μ-agonist) | Ratio method, BPND/VOI/n = 10 in luteal and in follicular phases. | No significant differences in μ-OR binding between phases of the menstrual cycle. A negative correlation between circulating levels of estradiol during the follicular phase and μ-OR measures in amygdala and hypothalamus, regions regulating GnRH pulsatility. LH pulse amplitude was positively correlated with μ-OR in the amygdala, whereas LH pulse number was negatively correlated with μ-OR in this same region. | These results suggest that amygdalar μ-ORs exert a modulatory effect on GnRH pulsatility, and that circulating levels of estradiol also regulate central μ-OR function. |
| Zubieta et al., 1999 | Examine age- and gender-associated variations in μ-OR binding. | [11C]CAF (μ-agonist) | Ratio method, BPND/VOI/n = 40 females, n = 36 males | μ-OR binding increase with age in neocortical areas and the putamen. Higher μ-OR binding in women was observed in a number of cortical and subcortical areas, but declined in postmenopausal women to levels below those of men. | These data imply that both age and gender are important variables of the OR system. |
| Cohen et al., 2000a | Gender differences in OR binding (healthy controls and AD patients). | [18F]FcyF (μ and κ-antagonist) | Ratio method, BPND/VOI/n = 9 females, n = 15 males | Less combined μ-/κ-OR binding in thalamus in females compared to males. | Consistent with evidence that sexual dimorphism exists with respect to opiate pathways. |
| Epilepsy: focal | |||||
| Frost et al., 1988 | Study role of μ-OR in temporal lobe epilepsy. | [11C]CAF (μ-agonist) and [18F]FDG (glucose metabolism) | Ratio method, BPND/VOI/n = 8 | Inter-ictal increased μ-OR binding in temporal neocortex and hypometabolism ipsilateral to epileptogenic focus. Hippocampus and amygdala had no change in binding or metabolism. | Opioids may represent an anticonvulsant system that limits spread of electrical activity. |
| Mayberg et al., 1991 | Study role of μ-OR (carfentanil) versus non-selective OR (diprenorphine) binding in temporal lobe epilepsy. | [11C]CAF(μ-agonist) and [11C]DPN (μ-, κ- and δ- antagonist) and [18F]FDG (glucose metabolism) | Ratio method, BPND/VOI/n = 11 | Inter-ictal μ-OR was increased in temporal neocortex and reduced in amygdala ipsilateral to epileptogenic focus. Non-selective OR binding exhibited no alteration. FDG showed temporal lobe hypometabolism. | The variation in pattern of carfentanil and diprenorphine binding supports a differential regulation of OR subtypes in unilateral temporal lobe epilepsy. |
| Theodore et al., 1992 | Study role of combined μ-/κ-OR binding in temporal lobe epilepsy. | [18F]FcyF (μ- and κ- antagonist) and H2[15O]O (perfusion) | Invasive compartment model, VT /VOI/n = 14 | Non-significant increased combined μ-/κ-OR binding and significant hypoperfusion in temporal lobe ipsilateral to epileptogenic focus. | Suggest that κ-OR are not involved in temporal lobe epilepsy, and therefore no significant asymmetry in combined μ-/κ-OR binding unlike Mayberg et al., 1991 who used a selective μ-OR agonist. |
| Bartenstein et al., 1994 | Study role of non-selective OR binding in temporal lobe epilepsy before and after surgery. | [11C]DPN (μ-, κ- and δ- antagonist) and [18F]FDG (glucose metabolism) | Ratio method, BPND/VOI/n = 2 patients n = 8 controls | Post-operative there was a reduced diprenorphine binding in the ipsilateral lateral temporal cortex. | Finding is compatible with downregulation of OR in lateral temporal lobe after removal of the epileptic focus. |
| Madar et al., 1997 | Study role of μ-OR (carfentanil) versus δ-OR (naltrindole) binding in temporal lobe epilepsy. | [11C-Me]Nal (δ-antagonist), [11C]CAF (μ-agonist) and [18F]FDG (glucose metabolism) | Ratio method, BPND/VOI/n = 10 | Both μ- and δ-OR binding was increased in the temporal cortex: μ-OR confined to middle aspect of inferior cortex, whereas δ-OR seen in mid-inferior cortex to anterior aspect of middle and superior temporal cortex. Hypometabolism was more widespread than changes in binding to either OR type. | Increase in delta receptors suggests their anticonvulsant action, and the different regional pattern of receptor alterations suggest the distinct roles of different opioid-receptor subtypes in seizure phenomena. |
| Hammers et al., 2007 | Investigate OR availability following spontaneous temporal lobe seizures. | [11C]DPN (μ-, κ- and δ- antagonist) | Invasive SA, VT /SPM + VOI/n = 9 patients × 2 scans (post-ictal and interictal), n = 14 controls × 2 scans | Increase in OR availability in the ipsilateral temporal pole during the postictal scan compared to control and inter-ictal scan. There was no reduced OR binding during the post-ictal scan. | Suggest an association of changes in endogenous opioid transmission with spontaneous seizures in temporal lobe epilepsy. |
| Koepp et al., 1998 | To localize dynamic changes in opioid neurotransmission associated with partial (reading) seizures. | [11C]DPN (μ-, κ- and δ- antagonist) | Invasive SA, VT /SPM/n = 5 patients, n = 6 controls | On activation scans (reading-baseline) OR-binding significantly lower left parieto-temporo-occipital cortex in reading-epilepsy patients compared with controls. | Opioid-like substances are involved in the termination of reading-induced seizures. |
| Epilepsy: absence seizure | |||||
| Bartenstein et al., 1993 | Study role of OR binding during absence seizure (ictal). | [11C]DPN (μ-, κ- and δ- antagonist) and H2[15O]O (perfusion) | Invasive compartment model, simulation/VOI/n = 8 | Increased elimination of diprenorphine from association cortex. | Suggest that endogenous opioids are released in the association cortex at the time of serial absences. |
| Prevett et al., 1994 | Study role of OR binding in absence seizure inter-ictally compared to healthy controls. | [11C]DPN (μ-, κ- and δ- antagonist) | Invasive SA, VT /VOI + SPM/n = 8 patients, n = 8 controls | No statistical difference between patients and healthy controls in diprenorphine binding. | Does not support an overall abnormality of opioid transmission, but does not exclude imbalance of receptor subtypes. |
| Movement disorders/neurodegeneration | |||||
| Burn et al., 1995 | Study differences in OR-binding between akinetic-rigid syndromes. | [11C]DPN (μ-, κ- and δ- antagonist) | Radio method, BPND/VOI/n = 8 PD, n = 7 SND, n = 6 SRO, n = 8 controls | Parkinson's disease was associated with no significant difference in binding compared to controls. Patients with striatonigral degeneration showed a reduced OR binding in putamen. Patients with Steele–Richardson–Olszewski syndrome (SRO) demonstrated reduced OR binding in both putamen and caudate nucleus. In single subject analysis, only in some patients the SRO group showed a reliably reduced binding. | There are differences in the pattern of OR binding in the patient groups that may help to differentiate these akinetic-rigid syndromes in life. |
| Cohen et al., 1998, 1999 | Role of OR in MPTP-lesion model of parkinsonism in monkeys. | [18F]FcyF (μ- and κ-antagonist) | Ratio method, BPND/VOI/n = 4 bilateral lesioned, n = 4 unilateral lesioned, n = 9 controls | Reduced OR-binding in caudate, anterior putamen, thalamus and hypothalamus bilaterally in both uni and bilat lesioned animals. | Endogenous opiates contribute to the phenotype of Parkinson's disease. |
| Piccini et al., 1997 | To determine whether the OR system is involved in levodopa-induced dyskinesias in Parkinson's disease. | [11C]DPN (μ-, κ- and δ- antagonist) | Ratio method, SA, VT, IRF60/VOI + SPM/n = 13 patients, 6 with dyskinesia n = 10 controls | Significantly reduced striatal and thalamic opioid binding in dyskinetic, but not in non-dyskinetic, PD patients. SPM analysis disclosed additionally decreased cingulate and frontal cortical binding in dyskinetic patients. | Confirm that altered opioid transmission is part of the pathophysiology of levodopa-induced dyskinesias in Parkinson's disease. |
| Whone et al., 2004 | Investigate OR binding in DYT1 primary torsion dystonia. | [11C]DPN (μ-, κ- and δ- antagonist) | Invasive SA, VT /SPM/n = 7 patients, n = 15 controls | No difference in diprenorphine binding was found between DYT1 primary torsion dystonia patients and controls, and no correlation between the severity of dystonia and opioid binding. | Aberrant opioid transmission is unlikely to be present in DYT1 primary torsion dystonia. |
| von Spiczak et al., 2005 | Investigate OR binding in relation to sensory and motor symptoms in restless legs syndrome (RLS). | [11C]DPN (μ-, κ- and δ- antagonist)) | Invasive SA, VT /SPM/n = 15 patients, n = 12 controls | No differences in OR binding between patients and controls. Regional negative correlations between OR binding and motor symptoms (thalamus, amygdala, NC, ACC, insula and orbitofrontal cortex) and pain scores (orbitofrontal cortex and ACC). | Suggest a central nervous system involvement of opioids in the pathophysiology of RLS. Pain is an underlying problem in RLS patients and suggested that motor symptoms in RLS are secondary to sensory symptoms. |
| Weeks et al., 1997 | Opioid neuronal loss is involved in the degenerative process of Huntington's disease. | [11C]DPN (μ-, κ- and δ- antagonist) | Ratio method, SA/VOI + SPM/n = 5 HD, n = 9 controls | Decrease in caudate and putamen OR binding compared to controls. SPM revealed additional non-hypothesized changes in cingulate and frontal cortices and thalamic areas. | Confirm that altered opioid transmission is part of the pathophysiology early Huntington's disease. SPM analysis is a viable alternative to conventional VOI analysis. |
| Cohen et al., 2000b | Examine responses in OR binding to neurodegeneration in a lesion model of the visual system in monkeys. | [18F]FcyF (μ- and, κ-antagonist) | Invasive, compartment model, VT /VOI/n = 6 lesioned with (4) and without (2) optical tract involvement. Scanned after 2–3 years n = 9 controls | The animals with the optic tract lesion had significantly higher OR binding in the lateral cortex, cingulate gyrus and posterior putamen. In both lesion groups, OR binding was reduced in the medial cortex. | Reduced OR binding in medial cortex are axonal and transneuronal degeneration. Visual deprivation leads to extensive functional changes of neuronal circuitries involving the OR system. |
| Cohen et al., 1997 | Expected that OR avidity would be lower in patients with Alzheimer's disease than in normal controls. | [18F]FcyF (μ- and κ-antagonist) and H2[15O]O (perfusion) | Invasive, compartment model, VT /VOI/n = 12 patients, n = 12 controls | Global grey combined μ-/κ-OR-binding and global grey perfusion were found to be lower in the Alzheimer's patients compared to controls. A specific hypoperfusion was identified in the parietal cortex, but no significant regional changes in OR binding were found. | Neurodegeneration is the likely underlying process responsible for changes in combined μ-/κ-OR binding. |
| Pain: experimental, acute | |||||
| Zubieta et al., 2001 | Induced muscular (masseter) pain | [11C]CAF (μ-agonist) | Non-invasive Logan plot, BPND/SPM/n = 20 × 2 scans (placebo and pain) | Sustained pain induced the regional release of endogenous opioids interacting with μ-OR in a number of cortical and subcortical brain regions. Associated with reductions in the sensory and affective ratings of the pain experience, with distinct neuroanatomical involvements. | Evidence for the role of the μ-OR in the neurotransmission of the individual experience of pain. |
| Bencherif et al., 2002 | Experimental pain induced by topical application of capsaicin. | [11C]CAF (μ-agonist) | Ratio method, BPND/SPM/n = 8 × 2 scans | A pain-related decrease in brain μ-OR binding was observed in the contralateral thalamus. | The supraspinal μ-OR system is activated by acute pain and may play a substantial role in pain processing. |
| Sprenger et al., 2006a | OR binding studied during tonic, heat pain. | [18F]FDPN (μ-, δ- and κ-antagonist) | Non-invasive Logan plot, BPND/SPM/n = 12 × 2 scans (in and out pain) | Reduction of diprenorphine binding in limbic and paralimbic brain areas including the rostral ACC and insula, related to heat pain. | Direct evidence for the involvement of rostral ACC in endogenous opioidergic inhibition of pain. |
| Zubieta et al., 2002 | Study of gender differences. Induced muscular (masseter) pain. | [11C]CAF (μ-agonist) | Non-invasive Logan plot, BPND/SPM/n = 14 female, n = 14 male. All × 2 scans (placebo and pain) | Men demonstrated larger magnitudes of μ-OR activation than women in the anterior thalamus, ventral basal ganglia and amygdala. Women showed a stronger μ-OR activation during pain in the nucleus accumbens. | Men and women (follicular phase) differ in the magnitude and direction of response of the μ-OR system in distinct brain nuclei. |
| Smith et al., 2006 | Examination of pain-related μ-OR neurotransmission during low and high estrogen states in women. | [11C]CAF (μ-agonist) | Non-invasive Logan plot, BPND/SPM/n = 10 females × 2 scans (low and high estrogen state), n = 8 males × 1 scan | The high-estrogen state was associated with regional increases in baseline μ-OR binding and greater pain-related activation of opioid neurotransmission. The latter did not differ from that obtained in males. During low-estrogen state, reduced opioid tone was seen in thalamus, NA and amygdala, which was associated with hyperalgesic responses. | Demonstrate a significant role of estrogen in modulating endogenous opioid neurotransmission and associated psychophysical responses to pain. |
| Zubieta et al., 2003a | Study of gene (COMT) polymorphism in relation to pain response and μ-OR activation. | [11C]CAF (μ-agonist) | Non-invasive Logan plot, BPND/SPM/n = 29. All × 2 scans (placebo and pain) | Met158 allele homozygotes for COMT polymorphism showed diminished μ-OR responses to pain and increased pain ratings compared to heterozygotes. Opposite effects were observed in val158 homozygotes. | COMT val158met polymorphism influences the human experience of pain and may underlie inter-individual differences in the adaptation and responses to pain. |
| Zubieta et al., 2005 | Analgetic placebo and μ-OR neurotransmission. | [11C]CAF (μ-agonist) | Non-invasive Logan plot, BPND/SPM/n = 14 × 3 scans (baseline, pain and pain + placebo) | Placebo-induced activation of μ-OR-mediated neurotransmission was observed in left dorsolateral frontal cortex, rostral ACC, left NA and right anterior insula, and was paralleled by lower pain ratings. | Demonstrate that cognitive factors are capable of modulating physical and emotional states through the site-specific activation of μ-OR signalling |
| Pain: chronic, pathological | |||||
| Jones et al., 1994 | Investigation of rheumatoid arthritis patients in and out of pain in relation to OR binding. | [11C]DPN (μ-, δ- and κ-antagonist) | Invasive compartment model, VT /VOI/n = 4 × 2 scans (in and out of pain) | Out of pain was related to a general increase in diprenorphine binding and region-specific increases in frontal, cingulate and temporal cortices and straight gyrus. | There are substantial increases in occupancy by endogenous opioid peptides during inflammatory pain. |
| Jones et al., 1999 | Study OR binding in patients with trigeminal neuralgia pain before and after thermocoagulation therapy. | [11C]DPN (μ-, δ- and κ-antagonist) | Invasive SA, VT /SPM/n = 6 × 2 scans (in and out of pain) | In pain condition compared to out of pain the regional OR binding was reduced in frontal, insular, perigenual, mid-cingulate and inferior parietal cortices, basal ganglia and thalamus bilaterally. | Suggest an increased occupancy by endogenous opioid peptides during trigeminal pain. |
| Jones et al., 2004 | Study OR binding in patients with central neuropathic pain. | [11C]DPN (μ-, δ- and κ-antagonist) | Invasive SA, VT /SPM/n = 4 patients, n = 4 controls | Less OR binding in a number of cortical and sub-cortical structures that are mostly, but not exclusively, within the medial pain system. | Demonstration of reduced OR-binding capacity in neurons within the human nociceptive system in patients with central neuropathic pain. This may be a key common factor resulting in undamped nociceptor activity within some of the structures that are predominantly within the medial nociceptive system. |
| Willoch et al., 2004 | Investigate OR binding in patients with central post-stroke pain. | [11C]DPN (μ-, δ- and κ-antagonist) | Ratio method, BPND + SA, IRF60/SPM + VOI/n = 5 patients, n = 12 controls | Independently of localization of lesion there was reduced diprenorphine binding in contralateral thalamus, parietal, secondary somatosensory, insular and lateral frontal cortices, and along the midline in anterior cingulate, posterior cingulate and midbrain grey matter. | A single lesion associated with a characteristic pattern of reduced OR binding within the neural circuitry processing pain. |
| Maarrawi et al., 2007 | Investigate the differences in OR binding between patients with central and peripheral neuropathic pain. | [11C]DPN (μ-, δ- and κ-antagonist) | Ratio method, BPND/SPM/n = 7 + 8 patients with peripheral neuropathic + central post-stroke pain, n = 15 controls | Patients with central post-stroke pain showed predominantly contralateral reductions in OR binding, whereas patients with peripheral neuropathic pain did not show any lateralized decrease in OR binding. | Difference in distribution of brain opioid system changes between peripheral neuropathic and central post-stroke pain suggest an opioid loss or inactivation in the central pain syndrome, and might explain their different sensitivity to opiates. |
| Sprenger et al., 2006b | Study of OR binding in patients with cluster headache, in bout but out of attack. | [11C]DPN (μ-, δ- and κ-antagonist) | Invasive SA, IRF60/SPM/n = 7 patients, n = 8 controls | Decreased overall OR binding in the pineal gland of cluster headache patients compared to controls. Opioid receptor availability in the hypothalamus and ACC depended on the duration of the headache disorder. | The pathophysiology of cluster headache may relate to opioidergic dysfunction in circuitries generating the biological clock. |
| von Spiczak et al., 2005 | Investigate OR binding in relation to sensory and motor symptoms in restless legs syndrome (RLS). | See above Movement disorder/Neurodegeneration. | |||
| Affective states | |||||
| Zubieta et al., 2003b | Dynamic changes in μ-OR binding related to induction of a state of sadness. | [11C]CAF (μ-agonist) | Non-invasive Logan plot, BPND/SPM/n = 14. All × 2 measurements (neutral and sad state) | Sustained sadness compared to neutral state showed increased μ-OR binding in ACC, pallidum, amygdala and inferior temporal cortex. Changes in μ-OR binding were correlated to increase in negative affect ratings. | The responses confirm the role of the μ-OR system in the physiological regulation of affective experiences in human. |
| Kennedy et al., 2006 | Affection: involvement of μ-OR neurotransmission in major depression and treatment response. | [11C]CAF (μ-agonist) | Non-invasive Logan plot, BPND/SPM/n = 14 patients, n = 14 controls. All × 2 measurements: sadness and neutral state | Differences in μ-OR availability between women with major depression and control women in neutral state and opposite responses in opioid neurotransmission during induced sadness. | The neurotransmission on μ-OR system, which is implicated in stress responses and emotional regulation, is altered in patients with major depression. |
| Liberzon et al., 2006 | Study of μ-OR after psychological trauma. | [11C]CAF (μ-agonist) | Non-invasive Logan plot, BPND/SPM/n = 16 patients, n = 14 (trauma) + 15 (non-trauma) controls. | Trauma groups had lower μ-OR binding in amygdale, nucleus accumbens and dorsal frontal and insular cortices, but higher μ-OR binding in orbitofrontal cortex. Patients had reduced μ-OR in the ACC compared to both control groups. | There are general trauma-related responses and specific post-traumatic changes in the μ-OR system. |
| Addiction | |||||
| Zubieta et al., 1996 | Opioids are involved in the reinforcing actions of cocain. Study of cocain craving. | [11C]CAF (μ-agonist) | Ratio method, BPND/VOI/n = 10 patients × 2 scans, n = 7 controls | Mu opioid binding was increased in several brain regions of the cocaine addicts studied 1–4 days after last use of cocaine and persisted after 4 weeks. Binding was positively correlated with the severity of cocaine craving experienced at the time. | Demonstrate the involvement of the endogenous OR system in cocaine dependence and cocaine craving. |
| Gorelick et al., 2005 | Study μ-OR binding in cocaine abstinence and in relation to craving over an extended time period. | [11C]CAF (μ-agonist) | Non-invasive Logan plot, BPND/VOI/n = 17 patients × 3 scans (1 day, 1 week and 12 weeks), n = 16 controls. | After 1 day of abstince μ-OR binding was increased in several areas of the FC and in ACC. FC, ACC and lateral temporal cortex. After 12 weeks of abstinence increased binding was only seen in anterior FC and ACC. Self-reported cocaine craving was associated with μ-OR in several brain regions until after 1 week of abstincence. (No reported craving at 12 weeks) | Mixed pattern of normalizing and persistent increased μ-OR binding suggests that there might be both state and trait relationships. |
| Scott et al., 2007b | Effects of nicotine from smoking cigarettes in humans on μ -opioidergic (and dopaminergic) neurotransmission. | [11C]CAF (μ-agonist) and [11C]raclopride (dopamine-D2 receptor antagonist) | Non-invasive Logan plot, BPND/SPM/n = 6 smokers × 2 measurements in one scan: before and during smoking, n = 6 non-smokers | Smokers have lower μ-OR binding during denicotinized cigarette condition compared to non-smokers in ACC, thalamus, ventral basal ganglia and amygdala. These reductions were reversed during smoking in thalamus, ventral basal ganglia and amygdale. A reduced binding was observed in parts of the ACC during smoking. Dopamine neurotransmission was activated in the ventral basal ganglia. | Smoking is related to changes in μ-OR availability and is paralleled by changes in dopamine neurotransmission. |
| Bencherif et al., 2004 | Study relationship between alcohol craving and μ-OR in alcohol-dependent subjects. | [11C]CAF (μ-agonist) | Ratio method, BPND/SPM/n = 8 patients, n = 8 controls | Alcohol-dependent subjects showed association with higher craving and lower μ-OR binding compared with control subjects in right dorsal lateral frontal cortex, the right anterior frontal cortex, and right parietal cortex. | There is a functional relationship between alcohol craving, mood and μ-OR binding in specific brain regions of recently abstinent, alcohol-dependent men. |
| Heinz et al., 2005 | Study of μ-OR changes after alcholism detoxification and in relation to craving | [11C]CAF (μ-agonist) | Non-invasive Logan plot, BPND/VOI + SPM/n = 25 patients (n = 12 rescanned after 5 weeks), n = 10 controls | After 1–3 weeks of abstinence μ-OR binding was increased in the ventral striatum compared to controls and remained elevated after 5 weeks. Higher μ-OR binding correlated positively with intensity of alcohol craving. | There is increased μ-OR binding in alcohol detoxified patients within a neural network that has been associated with drive states and drug craving. |
| Ingman et al., 2005 | Study of pharmacokinetics and μ-OR occupancy of nalmefene after single and repeated dosing over 7 days. | [11C]CAF (μ-agonist) | Non-invasive Logan plot, BPND/VOI/n = 12 × 3 scans, all before drug and 2 each at 3, 26, 50 or 74 h after single drug intake, and all after 7 days of repeated dosing. | High nalmefene occupancy (83–100%) persisted at 26 h after the dosings, and decline in the occupancy was clearly slower than the decline in the plasma concentration of nalmefene or metabolites. | The slow dissociation of drug from μ-OR suggest that a high receptor occupancy can be maintained when nalmefene is taken once daily. |
| Kling et al., 2000 | Investigation of methadone treatment in heroin addicts. | [18F]FcyF (μ- and κ-antagonist) | Invasive compartment model, VT/VOI/n = 14 patients, n = 14 controls | Combined μ-/κ-OR binding in thalamus, amygdala, caudate, anterior cingulate cortex and putamen was significantly reduced (19–32%). Methadone plasma levels correlated to receptor occupancy in caudate and putamen. | Lower levels of μ-/κ-OR binding may be related to receptor occupancy with methadone and that significant numbers of OR may be available to function in their normal physiological roles. |
| Melichar et al., 2005 | Study relationship between methadone dose and OR in heroin dependent patients | [11C]DPN (μ-, δ- and κ-antagonist) | Invasive SA, VT/VOI/n = 8 patients, n = 8 controls + animal studies | No difference in diprenorphine binding was found between the groups, with no relationship between methadone dose and occupancy either given chronically in humans or acutely in rats. | Suggest high efficacy of methadone at very low levels of OR occupancy. |
| Greenwald et al., 2003 | Study of heroin-dependence and buprenorphine treatment | [11C]CAF (μ-agonist) | Non-invasive Logan plot, BPND/VOI/n = 14 patients. (5 completed all 4 scans at 0, 2, 16 and 32 mg buprenorphine). | μ-OR availability decreases were negatively correlated with BUP plasma level and positively correlated with questionnaire-based opioid withdrawal symptoms. Over 90% receptor occupancy at doses of 32 mg buprenorphine. | Suggest that high-dose buprenorphine maintenance produces near-maximal μ-OR occupation and μ-OR availability correlates well with plasma levels. |
| Greenwald et al., 2007 | Study of buprenorphine duration of action | [11C]CAF (μ-agonist) | Non-invasive Logan plot, BPND/VOI/n = 10 × 4 scans (4, 28, 52 and 76 h after last buprenorphine dose) | Whole-brain μ-OR availability increased from 30%, 54%, 67% to 82% after 4, 28, 52 and 76 h, respectively, of last buprenorphine dose. μ-OR binding correlated with plasma concentration, withdrawal symptoms and hydromorphone blockade. | The μ-OR availability predicts changes in pharmacokinetic and pharmakodynamic measures, and ∼50–60% receptor occupancy of buprenorphine is required for adequate withdrawal symptom suppression. |
| Eating disorder | |||||
| Bencherif et al., 2005 | Study μ-OR in bulimia nervosa as the OR system has been implicated in feeding behaviour. | [11C]CAF (μ-agonist) | Ratio method, BPND/SPM/n = 8 patients, n = 8 controls | μ-OR binding in the left insular cortex was less in bulimic subjects than in controls and correlated negatively with recent fasting behaviour. | μ-OR binding in the insula may be important in the pathogenesis or maintenance of the self-perpetuating behavioural cycle of bulimic subjects. |
The consensus nomenclature for PET receptor binding has been used throughout the table (Innis et al., 2007).