529 NEUROIMAGING CLINICS OF NORTH AMERICA Neuroimag Clin N Am 16 (2006) 529–552 Opioid Imaging Alexander Hammers, PhDa,b,c,*, Anne Lingford-Hughes, PhDd,e - Derivation, release, peptide action, Changes in receptor availability in pain and metabolism and discomfort: between-group - Receptors and ligands comparisons Receptors Direct intrasubject comparisons of periods Species differences with pain and pain-free states Regional and layer-specific subtype - Opioid imaging in epilepsy distributions Focal epilepsies Ligands Idiopathic generalized epilepsy - Positron emission tomography imaging Summary of opioid receptors - Opioid imaging in other specialties Introduction PET imaging Movement disorders Quantification of images Dementia Available ligands and their quantification Cardiology - Opioid receptor imaging in healthy - Opioid imaging in psychiatry: addiction volunteers - Summary - Opioid imaging in pain-related studies - Acknowledgments - References Opioids derive their name from the Greek o´pioy agonists provided evidence for the existence of mul- for poppy sap. Various preparations of the opium tiple receptors [4]. In the early 1980s, there was ev- poppy Papaver somniferum have been used for pain idence for the existence of at least three types of relief for centuries. Structure and stereochemistry opiate receptors: m, k, and d [5,6]. A fourth ‘‘orphan’’ are essential for the analgesic actions of morphine receptor (ORL1 or NOP1) displays a high degree and other opiates, leading to the hypothesis of the of structural homology with conventional opioid existence of specific receptors. Receptors were iden- receptors and was identified through homology tified simultaneously by three laboratories in 1973 with the d receptor [7], but the endogenous ligand, [1–3]. The different pharmacologic activity of orphanin FQ/nociceptin, does not interact directly Dr. Hammers was funded by an MRC Clinician Scientist Fellowship (G108/585). a Department of Clinical Neuroscience, Division of Neuroscience and Mental Health, Imperial College London, Hammersmith Hospital, DuCane Rd., London W12 0NN, UK b Epilepsy Group, MRC Clinical Sciences Centre, Room 243, Cyclotron Building, Hammersmith Hospital, DuCane Rd., London W12 0NN, UK c Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK d Academic Unit of Psychiatry, University of Bristol, Cotham House, Cotham Hill, Bristol BS6 6JL, UK e Imaging Department, Division of Clinical Sciences, Faculty of Medicine, Hammersmith Hospital, Imperial College London, DuCane Rd., London W12 0NN, UK * Corresponding author. Epilepsy Group, MRC Clinical Sciences Centre, Room 243, Cyclotron Building, Hammersmith Hospital, DuCane Rd., London W12 0NN, UK. E-mail address: [email protected] (A. Hammers). 1052-5149/06/$ – see front matter ª 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.nic.2006.06.004 neuroimaging.theclinics.com 530 Hammers & Lingford-Hughes with classical opioid receptors [8] and is not dis- leads to receptor desensitization, and long-term ex- cussed further herein. Endogenous opioids have posure to agonists leads to receptor downregulation been identified [9]. These substances were origi- [17]. Desensitization is achieved through phos- nally distinguished from exogenous opiates, but phorylation of agonist-activated receptors and sub- the term opioids is now generally used for all ligands. sequent receptor endocytosis via clathrin-coated Besides their role as endogenous and exogenous pits. The ubiquitin/proteasome pathway seems to pain killers, opioids and their receptors are impli- be important in agonist-induced downregulation cated in reward, addiction, mood regulation and as well as basal turnover of opioid receptors. Mono- mood disorders, epilepsy, movement disorders, ubiquinated receptors are simply internalized, and dementia. whereas ubiquitin chains of more than three units target the receptor to the proteasome. Further down- stream, trafficking to lysosomes may have a role. Derivation, release, peptide action, Triggered release of endogenous opioids (eg, in and metabolism seizure models) leads to major changes [18]. In lab- All opioid peptides are derived from three different oratory animals, transmitter peptide levels generally gene products: proopiomelanocortin, proenkepha- decrease to about 40% to 50% of baseline in the lin, and prodynorphin. Proopiomelanocortin gives hours after release. Levels of transmitter peptide rise to b-endorphin (m- and d- preferring) and non- mRNA tend to increase temporarily. Depending opioid peptides. Proenkephalin contains four cop- on the model, increases can be relatively minor (ap- ies of different enkephalins (most d-preferring). proximately 150% of baseline) or major (300% to Prodynorphin gives rise to several dynorphin pep- 1400%). Limited data are available on opioid recep- tides and neoendorphin (all k-preferring) (Table 1) tor level changes following events like epileptic sei- [10]. Endogenous opioids consist of between zures. Acute release leads to decreased availability of four (endomorphin) and 31 amino acids (b- receptors as measured by [3H]diprenorphine bind- endorphin). ing [13] or [3H]U69,593 binding [14]. Over slightly Similar to other neuropeptides, opioids are stored longer time courses, both decreases, particularly for in large dense core vesicles [11], which are distin- d-opioid receptors [19], and increases (of the m re- guishable electron microscopically from small clear ceptor) [20] have been found. Receptor endocytosis vesicles containing the fast-acting transmitters such may be irreversible for d receptors, requiring de as GABA and glutamate. Opioid vesicle containing novo protein synthesis [17]. neurons also contain classical fast-acting transmit- Opioid receptor function changes over the hours ters; therefore, opioids act as co-transmitters to following neuronal events have received far less at- modulate the actions of the primary transmitter. tention. After 4 hours of exposure to the m-agonist Exocytosis of the dense core vesicles is calcium de- DAMGO to induce desensitization, some func- pendent [12] but, unlike small clear vesicles, exocy- tional resensitization of the m receptor occurred tosis is not limited to restricted zones of the plasma after 10 minutes, with 100% of control responses membrane. Exocytosis requires high-frequency stim- reached after 60 minutes [21]. In another study, ulation of the opioid-containing neurons [13,14]. m-receptor protein reached normal levels and func- In contrast to amino acid transmitters, opioid tion after 6 hours through recycling [22]. Basal peptides can affect the excitability of neurons at levels can be achieved through recycling in 30 the relatively large distance of 50 to 100 mm from [23] to 60 minutes, with some agonists inducing the site of release [15] owing to their diffusion receptor levels of 110% to 120% of control as mea- through the extracellular space and their high affin- sured with [3H]diprenorphine [24]. ities for their receptors, with nanomolar concentra- tions of the peptides being effective [16]. After Receptors and ligands release from nerve terminals, opioid peptides are rapidly degraded by a variety of peptidases [9]. Receptors The time courses of changes of transmitter pep- There are three main types of opioid receptors, m, d, tides and receptor protein are of great interest and k. For all, the existence of subtypes has been when interpreting positron emission tomography proposed [10], and one subtype each has been (PET) studies of opioid function in experiments de- cloned in several species including man. The recep- signed to show the role of neurotransmitters, usu- tor proteins consist of about 370 amino acids [17]. ally by employing two PET scans acquired at They belong to the G-protein coupled receptor fam- different delays from an experimental manipula- ily and have their characteristic structure with seven tion or spontaneously occurring event. hydrophobic transmembrane domains, connected As is true for most G-protein coupled receptors, by relatively short intracellular and extracellular short-term exposure of opioid receptors to agonists loops. The amino acid sequences are about 60% Opioid Imaging 531 Table 1: Opioid receptors and their ligands Receptor m (MOR) d (DOR) k (KOR) Endogenous b-endorphin > b-endorphin, Dynorphin A >> ligand potency dynorphin A > leu-enkephalin, b-endorphin > met-enkephalin, met-enkephalin > leu-enkephalin > leu-enkephalin dynorphin A met-enkephalin Agonists DAMGO DPDPE Enadoline (CI-977) DAGO DSLET U69,593 Dihydromorphine DADLE (d, m) Selective CTAP Naltrindole nor-BNI antagonists Nonselective Naloxone antagonists Naltrexone (orally active) PET ligands Abbreviations: DAMGO, [D-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin; DAGO, D-Ala2-MePhe4-Gly(ol)5 enkephalin: DPDPE, [D-Pen2,5]-enkephalin; DSLET, [D-Ser2, Leu5] enkephalin-Thr6; DADLE, D-Ala2-D-Leu5 enkephalin; CTAP, D-Phe-Cys- Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2; nor-BNI, nor-binaltorphimine. 532 Hammers & Lingford-Hughes identical between opioid receptor types and about (except medial occipital), as well as some midbrain 90% identical between the same receptor types and deeper nuclei [31]. m-opioid receptor binding is cloned from different species. There are marked present in all of these areas but is most dense in differences in the degree of sequence conservation layers I, IIIa, and IV [26,28,29], suggesting a somato- between domains. Most transmembrane segments dentritic expression. Functional