Opioids, Reward and Addiction: An Encounter of Biology ...

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342 VAN REE ET AL. IX. Perspectives ........................................................................... 384 X. References ............................................................................ 384 I. Introduction If the entire materia medica at our disposal were limited to the choice and use of only one drug, I am sure that a great many, if not the majority, of us would choose opium (Macht, 1915). A. Early History Opium is the dried milky juice of the unripe seed capsule of the poppy, the Papaver somniferum. The word opium is derived from “opos”, the Greek word for juice. The first reference to this juice was by Theophrastus (300 B.C.), mentioning it mekonion. The medicinal and nonmedicinal use of opium by the ancient Greeks and Romans is not well documented, but it is generally believed that they were aware of the euphoric and narcotic (from the Greek word for stupor) properties of opium. They probably also knew that it could be applied for pain relief and dysentery. There are suggestions that the opium poppy was cultivated in Persia back to the end of the third millennium B.C. Arabic physicians used opium quite often and Arabic traders brought opium from the eight century A.D. on, first to the East, to India and China, and later to Europe. The Mohammedan prohibition of wine and the banning of tobacco smoking in China may have favored the spread of opium. With the “worldwide” availability of opium, the phenomenon addiction raised its head. An attempt to forbid the import of opium into China by the authorities, led to the socalled “Opium War” between England and China, with the result that opium trade was permitted (Macht, 1915). Medicinal use of opium was stimulated by the famous physician Paracelsus at the end of the middle ages by the introduction of tincture of opium or laudanum. The name laudanum is probably derived from the Latin “laudandum”, which means something to be praised. Several preparations of laudanum were made, all of which contained more or less opium and many other ingredients. Laudanum and other preparations of opium (e.g., extracts of opium and pilulae opii) were widely used for a number of indications. In the beginning of the 19th century, the pharmacist Sertürner isolated an important active principle of opium, the alkaloid morphine (Sertürner, 1806). Morphine was named after the Greek god of dreams, Morpheus. During the nineteenth century many other alkaloids were isolated from opium, some of them with a comparable, but weaker action than morphine and others with a different pharmacological profile. From the mid-nineteenth century on, morphine was parenterally administered as premedication for surgical procedures and for postoperative and chronic pain. Morphine appeared to be as addictive as opium. This stimulated research to develop nonaddictive opiates, substances with the beneficial therapeutic actions of morphine but lacking its addictive potential. In 1898, heroin was introduced as the ideal nonaddictive substitute for morphine. It lasted quite a long time before it became clear that heroin has a higher addictive potential than morphine. Several claims for nonaddictive opiates followed, but to date, none of these claims have been substantiated. During the 20th century a number of drugs were synthesized with a morphine-like action, but with a structure somewhat different from that of morphine. Examples are meperidine (1939) and methadone (1946). Structure-activity studies with the morphine molecule as starting point resulted in the synthesis of nalorphine, a mixed agonist-antagonist: the drug reverses the typical actions of morphine and it precipitates the abstinence syndrome in opiate addicts, but it also has analgesic properties. Additional research led to the discovery of pure opiate antagonists such as naloxone. B. Opioid Receptors and Endogenous Opioids The structural similarities between all substances with an opiate-like action and the discovery of opiate agonists, mixed agonist-antagonists and antagonists, generated the concept of opiate receptors. Goldstein et al. (1971) used radiolabeled levorphanol to discover opiate-binding sites in subcellular fractions of mouse brain. When radioligands with high specific activity became available, stereospecific opiate-binding sites in the central nervous system were demonstrated (Pert and Snyder, 1973; Simon et al., 1973; Terenius, 1973). The finding of opiate-binding sites and the fact that opiate antagonists exerted some intrinsic activity in opiate naive subjects and could diminish nondrug-induced analgesia stimulated thoughts about endogenous compounds with opiate-like action (Lasagna, 1965; Jacob et al., 1974; Akil et al., 1976; Buchsbaum et al., 1977). In this review, the term opioid will be used for all substances with an opiate-agonistic action. Endogenous and exogenous opioids can be distinguished, depending on whether the substances are normally present in the body or not. The first indication for endogenous opioids came from studies showing that brain extracts contain opioidlike activity (Terenius and Wahlström, 1974; Kosterlitz and Waterfield, 1975). Further investigations led to the isolation and characterization of the enkephalins (from the Greek “in the head”), the first discovered endogenous opioids (Hughes et al. 1975). There appeared to be two pentapeptides, Met- and Leu-enkephalin. The structure of Met-enkephalin was also present as the N-terminal part of the earlier isolated C fragment, part of the fat-mobilizing
pituitary hormone -lipotropin (Bradbury et al., 1976). The C fragment, later termed -endorphin (from endogenous morphine), and the enkephalins were shown to induce similar actions as morphine in a number of in vitro and in vivo test procedures. Repeated administration of -endorphin led to tolerance to its analgesic action and to morphine-like withdrawal symptoms upon a challenge with naloxone (Van Ree et al., 1976; Wei and Loh, 1976). Furthermore, -endorphin and the enkephalins were self-administered by laboratory animals, indicating the rewarding properties and addictive potential of these substances (Belluzzi and Stein, 1977; Van Ree et al., 1979; Goeders et al., 1984). Thus, the endogenous opioids may share all its typical opioid-like actions with morphine, both after acute and chronic administration. After the discovery of another class of endogenous opioids, the dynorphins, (dyn.... from Greek dynamis power) (Goldstein et al., 1979, 1981), it appeared that most endogenous opioids are generated by enzymatic processing from three precursor molecules, pro-opiomelanocortin (POMC), 2 proenkephalin (ProEnk), and prodynorphin (ProDyn) (Nakanishi et al., 1979; Kakidani et al., 1982; Noda et al., 1982). Each of these precursors has an unique anatomical distribution throughout the central nervous system (CNS) and in peripheral organs (Akil et al., 1984; Khachaturian et al., 1985). The anterior and neurointermediate lobes of the pituitary gland are major sites of POMC biosynthesis. In the brain, there are two distinct nuclei that contain POMC neurons: the arcuate nucleus of the hypothalamus and the nucleus tractus solitarius. Widespread projections from these neurons are present throughout the brain. From POMC the opioid -endorphin is generated, but also - and -endorphin and several nonopioid peptides, e.g., adrenocorticotropin and - and -melanocyte-stimulating hormones. ProEnk-containing neurons are widely distributed throughout the brain and consist of both local circuits and long projection neurons. ProEnk is the source of Leu- and Met-enkephalin and several extended forms of these pentapeptides. ProDyncontaining cell bodies have a characteristic widespread distribution throughout the CNS. ProDyn-containing neurons have both short and long projection pathways and 2 Abbreviations: POMC, pro-opiomelanocortin; 5-HT, 5-hydroxytryptamine (serotonin); ICSS, intracranial electrical self-stimulation; 6-OHDA, 6-hydroxydopamine; i.c.v. intracerebroventricular; AMPA, -amino-3-hydroxy-5-methylisoxazole-4-propionic acid; E- IR, -endorphin immunoreactivity; LAAM, l--acetylmethadol; LH, lateral hypothalamus; BNTX, 7-benzylidenenaltrexone; MFB, medial forebrain bundle; CCK, cholocystokinine; NAC, nucleus accumbens; CNS, central nervous system; NMDA, N-methyl-D-aspartate; CTOP, D-Phe-Cys-Tyr-D-Trp-Orn-Thr- Phe-Thr-NH 2; nor-BNI, norbinaltorphimine; DA, dopamine; ProEnk, pro-enkephalin; DAMGO, [D-Ala, N-Me-Phe 4 , Gly-ol 5 ]-enkephalin; PAG periaquaductal gray; DNQX, 6,7-dinitroquinoxaline-2,3-dione; ProDyn, pro-dynorphin; DPDPE, [D-Pen 2 , D-Pen 5 ]-enkephalin; TIQ, tetrahydroisoquinoline; VTA, ventral tegmental area; FR, fixed-ratio; HAD, high alcoholdrinking; AA, alko alcohol; DG-AVP, desglycinamide 9 -[Arg 8 ]-vasopressin. OPIOIDS, REWARD AND ADDICTION 343 can generate several opioid peptides, including - and -neoendorphin, dynorphin A, and dynorphin B. Martin et al. (1976) first postulated the existence of multiple types of opioid receptors. Based on their behavioral and neurophysiological findings in the chronic spinal dog, they distinguished between the type (for morphine, which induces analgesia, hypothermia, and meiosis among others), the -type (for ketocyclazocine, which induces depression of flexor reflexes and sedation among others), and -type (for SKF10,047 or N-allylnormetazocine, which induces tachycardia, delirium, and increased respiration among others). Later, a fourth type of opioid receptor, named (for vas deferens) was identified (Lord et al., 1977). Additional research revealed that the -type receptor is nonopioid in nature, leaving three main type of opioid receptors, , , and (Mannalack et al., 1986). These receptors, belonging to the family of seven transmembrane G protein-coupled receptors, have been cloned using molecular biological techniques (Evans et al., 1992; Kieffer et al., 1992; Reisine and Bell, 1993; Uhl et al., 1994; Knapp et al., 1995). Apart from occurring as separate molecules, brain - and -opioid receptors have also been suggested to function as a - receptor complex (for review, see Rothman et al., 1993). In slices of rat neostriatum, activation of this complex, which displays an affinity profile for opioid ligands different from nonassociated - and -opioid receptors, has been shown to inhibit dopamine (DA) D1-receptor-stimulated adenylate cyclase activity (Schoffelmeer et al., 1992, 1993). Interestingly, there seems to be some preference for the different endogenous opioid ligands for the different receptors: -endorphin for , enkephalins for , and dynorphins for . Subtypes of these receptors have been proposed ( 1, 2; 1, 2; 1, 2, 3) (Dhawan et al., 1996) and some evidence is available for some other receptor types [e.g., the receptor which was labeled as -endorphin specific (Wüster et al., 1979; Narita and Tseng, 1998)]. The International Union of Pharmacology subcommittee on opioid receptors has proposed another terminology to distinguish the opioid receptors: OP1, OP2, and OP3 for the , , and receptor, respectively (Dhawan et al., 1996) (Table 1). Another opioid-like receptor has been cloned, termed the ORL-1 opioid receptor (Fukuda et al., 1994; Mollereau et al., 1994; Lachowitz et al., 1995). In addition, some novel endogenous opioids have been isolated, termed orphanin FQ which seems to be an endogenous ligand for ORL-1 and endomorphin-1 and endomorphin-2 which have been pro- TABLE 1 Nomenclatures of opioid receptors (IUPHAR recommendations) Preferential Endogenous Opioid Ligands IUPHAR Recommendation Opioid Receptors Pharmacology Nomenclature Molecular Biology Nomenclature Enkephalins OP1 DOR Dynorphins OP2 KOR -endorphin OP3 MOR See Dhawan et al. (1996).
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