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Opioid Peptides and Their Receptors: Overview and Function in Pain Modulation

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Opioid Peptides and Their Receptors: Overview and Function in Pain Modulation 3 OPIOID PEPTIDES AND THEIR RECEPTORS: OVERVIEW AND FUNCTION IN PAIN MODULATION GAVAN P. MCNALLY AND HUDA AKIL Few neurotransmitter systems have fascinated the general information we possess on the endogenous opioid system. public as much as the endorphins, otherwise known as the However, we attempt to give the reader key information endogenous opioid peptides. They have been termed the ‘‘her- about the biochemical nature of the system, along with an oin within’’ and endowed with the power to relieve pain update on our understanding of the recently cloned recep- and allow one to experience ‘‘runner’s high’’ or enjoy the tors and their functions. Finally, we describe the regulation taste of chocolate. Although these powers may or may not of pain responsiveness as one example of a function me- withstand close scientific scrutiny, there is little question diated by opioids to illustrate the complexity of their role. that endogenous opioid systems play a critical role in modu- lating a large number of sensory, motivational, emotional, and cognitive functions. As inhibitory neuropeptide trans- mitters, they fine-tune neurotransmission across a wide OPIOID PEPTIDES AND THEIR RECEPTORS range of neuronal circuits, setting thresholds or upper limits. Genes and Proteins In addition, they have served as prototypes for understand- ing many structural and functional features of peptidergic The opioid peptide precursors are encoded by three genes: systems. Thus, the first neuronal receptor binding assays pre-proopiomelanocortin, pre-proenkephalin, and pre-pro- were conducted on opioid receptors. The first peptides to dynorphin. Each precursor is subject to complex post-trans- be discovered and identified after the hypothalamic neuro- lational modifications that result in the synthesis of multiple hormones (oxytocin and vasopressin) were the endogenous active peptides. These peptides share the common N-termi- opioids. The first mammalian cyclic DNA(cDNA)to be nal sequence of Tyr-Gly-Gly-Phe-(Met or Leu), which has cloned was an opioid precursor (proopiomelanocortin), been termed the opioid motif; this is followed by various C- which also served as the prototype for genes that encode terminal extensions yielding peptides ranging from 5 to 31 multiple active substances and process them in a tissue- residues in length. The major opioid peptide encoded by ␤ ␤ specific and situation-specific manner. pre-proopiomelanocortin is -endorphin. In addition to - Scientific studies of these systems during the last 30 years endorphin, the proopiomelanocortin precursor encodes the have uncovered a complex and subtle system that exhibits nonopioid peptides adrenocorticotropic hormone (ACTH), ␣-melanocyte-stimulating hormone (␣-MSH), and ␤-lipo- impressive diversity in terms of the number of endogenous ␤ ligands (more than a dozen) yet amazing convergence at the tropic pituitary hormone ( -LPH). Pre-proenkephalin en- level of receptors (only three major types). Based on the codes multiple copies of Met-enkephalin, including two ex- results of these studies, the endogenous opioids have been tended forms of Met-enkephalin (a heptapeptide and an implicated in circuits involved in the control of sensation, octapeptide), and a single copy of Leu-enkephalin. Pre-pro- emotion, and affect, and a role has been ascribed to them dynorphin encodes three opioid peptides of various lengths in addiction—not only to opiate drugs, such as morphine that all begin with the Leu-enkephalin sequence: dynorphin A, dynorphin B, and neoendorphin (Fig. 3.1). and heroin, but also to other highly abused drugs, such as ␮ ␦ alcohol. This chapter cannot do justice to the rich body of The -opioid receptors (MORs), -opioid receptors (DORs), and ␬-opioid receptors (KORs) have been isolated and cloned. The mouse DOR receptor was the first opioid receptor cloned (1,2), and this initial cloning facilitated the Gavan P. McNally and Huda Akil: Mental Health Research Institute, rapid cloning of MOR and KOR from various rodent spe- University of Michigan, Ann Arbor, Michigan. cies (3–9). The coding regions of human genes for these 36 Neuropsychopharmacology: The Fifth Generation of Progress ProOrphanin ProDynorphin ProEnkephalin POMC FIGURE 3.1. The opioid-peptide precursors. (From Akil H, Owens C, Gutstein H, et al. Endogenous opioids: overview and current issues. Drug Alcohol Depend 1998;51:127–140, with permission.) receptors were subsequently isolated and chromosomally as- clear from studies of the cloned receptors that high-affinity signed (10–12). These studies confirmed earlier pharmaco- interactions between each of the precursor and receptor logic data indicating that all three receptors belong to the families are possible (14). For example, the proenkephalin superfamily of seven transmembrane-spanning G protein- peptide Tyr-Gly-Gly-Phe-Met-Arg-Phe binds with sub- coupled receptors. Ahigh degree of structural similarity ex- nanomolar affinity to each of the cloned receptors. Simi- ists between the three opioid receptors, which is highest in larly, although binding with greater affinity to the KOR, transmembrane domains 2, 3, and 7 and the first and second several of the shorter prodynorphin peptides bind with rea- intracellular loops. The extracellular loops diverge consider- sonable affinity to the MOR and DOR. By contrast, the ably among the three receptor classes, and this divergence binding of shorter proenkephalin peptides Leu-Enk (Tyr- may explain differences in ligand selectivity among the opi- Gly-Gly-Phe-Leu) and Met-Enk (Tyr-Gly-Gly-Phe-Met) oid receptors (Fig. 3.2). readily discriminates between the three receptor families. The relationship between the opioid peptides and their Overall, the KOR displays the greatest selectivity across the receptors is complex. This has been reviewed in detail else- endogenous ligands, with an approximately 1000-fold dif- where (13), and we will note only some salient features. It is ference in affinity between the most preferred (Dyn A1–7) and least preferred (Leu-Enk) ligand, whereas the MOR and DOR differ only across a 10-fold range (14). These differences in selectivity could indicate the existence of dis- tinct mechanisms for ligand recognition, such that MOR and DOR recognize the common Tyr-Gly-Gly-Phe core, whereas the KOR discriminates among the larger variation in C-terminal regions. Indeed, elegant studies in which re- ceptor chimeras were used have identified the critical do- mains in the three opioid receptors that help discriminate among the endogenous ligands (13). Further attempts to detect novel opioid receptors re- sulted in the isolation of a clone with high structural homol- ogy to the opioid clones but little or no binding affinity for FIGURE 3.2. The opioid receptors display a high degree of struc- tural similarity. Numbers refer to the percentages of amino acid the opioid ligands (15,16). The structural similarity be- identity between the cloned ␮-, ␦-, and ␬-opioid receptors. tween this orphan (or opioid receptor-like) opioid receptor Chapter 3: Opioid Peptides in Pain Modulation 37 (ORL-1) and the opioid receptors is highest in the trans- diversity: alternative splicing of receptor RNAand dimeriza- membrane regions and cytoplasmic domain and lowest in tion of receptor proteins. the extracellular domains critical for ligand selectivity (see Alternative splicing of receptor heteronuclear RNA (e.g., below). Aligand for the receptor was subsequently identi- exon skipping and intron retention) has been accorded an fied by two groups using chromatographic fractionation important role in producing in vivo diversity within many techniques coupled to ORL-1-mediated inhibition of ade- members of the superfamily of seven transmembrane-span- nylyl cyclase (17,18). This 17-amino acid peptide is iden- ning receptors (28). For example, alternative splicing of the tical in length and C-terminal sequence to dynorphin A. coding region for the N-terminus of the corticotropin-re- Curiously, the N-terminal is slightly modified (Phe-Gly- leasing hormone CRH-2 receptor results in ␣, ␤, and ␥ Gly-Phe) from the opioid core described above. It has been variants, each with a unique tissue distribution (see ref. 28 termed orphanin-FQ or nociceptin because of its putative for review). It follows that splice variants may exist within ability to lower pain thresholds. The orphanin-FQ/nocicep- each of the three opioid-receptor families and that this alter- tin (OFQ/N) precursor has been cloned from mouse, rat, native splicing of receptor transcripts may be critical for the and human and has been localized on the short arm of diversity of opioid receptors. Atechnique used extensively human chromosome 8 (19,20). In addition to OFQ/N, to identify potential sites of alternative splicing is antisense evidence suggests that this precursor may encode other bio- oligodeoxynucleotide (ODN) mapping. The ability of anti- logically active peptides. Immediately downstream to OFQ/ sense ODNs to target specific regions of cDNAallows sys- N is a 17-amino acid peptide (OFQ-2) that also starts with tematic evaluation of the contribution of individual exons phenylalanine and ends with glutamine but is otherwise to the observed properties of a receptor. Antisense ODN distinct from OFQ/N, and a putative peptide upstream targeting of exon 1 of the cloned rat and mouse MOR from OFQ/N may be liberated on post-translational pro- prevents morphine analgesia in these species (29–31). By cessing (nocistatin). The OFQ/N system is a distinct neuro- contrast, administration of antisense ODNs targeting exon peptide system with a high degree of sequence identity to the 2, which are inactive against morphine analgesia, prevents opioids. This slight change in structure results in a profound the analgesia produced by heroin, fentanyl, and the mor- alteration in function. Thus, OFQ/N is motivationally neu- phine metabolite morphine-6-␤-glucuronide (M6G) (29- tral, as indexed by conditioned place preference (21), and 31). Asimilar disruption of M6G but not morphine analge- has pain modulators distinct from those of the opioid pep- sia is observed following administration of antisense ODNs tides (see below). However, changes in as few as four amino targeting exon 3 (29).
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