Opioid and opioid-like receptors are activated by a variety of endogenous peptides including [Met]enkephalin (PENK, P01210) (met), [Leu]enkephalin (PENK, P01210) (leu), β-endorphin (POMC, P01189) (β-end), α-neodynorphin (PDYN, P01213), dynorphin A (PDYN, P01213) (dynA), dynorphin B (PDYN, P01213) (dynB), big dynorphin (PDYN, P01213) (Big dyn), nociceptin/orphanin FQ (PNOC, Q13519) (N/OFQ); endomorphin-1 and endomorphin-2 are also potential endogenous peptides. The Greek letter nomenclature for the opioid receptors, μ, δ and κ, is well established, and NC-IUPHAR considers this nomenclature appropriate, along with the symbols spelled out (mu, delta, and kappa), and the acronyms, MOP, DOP, and KOP [20-21,31]. However the acronyms MOR, DOR and KOR are still widely used in the literature. The human N/OFQ receptor, NOP, is considered 'opioid-related' rather than opioid because, while it exhibits a high degree of structural homology with the conventional opioid receptors [63], it displays a distinct pharmacology. Currently there are numerous clinically used drugs, such as morphine and many other opioid analgesics, as well as antagonists such as naloxone. The majority of clinically used opiates are relatively selective μ agonists or partial agonists, though there are some μ/κ compounds, such as butorphanol, in clinical use. κ opioid agonists, such as the alkaloid nalfurafine and the peripherally acting peptide difelikefalin, are in clinical use for itch.

Three genes for naloxone-sensitive opioid receptors have been identified in humans, and while the μ receptor in particular may be subject to extensive alternative splicing [69], these putative isoforms have not been correlated with any of the subtypes of receptor proposed in years past. Opioid receptors may heterodimerize with each other or with other 7TM receptors [45], and give rise to complexes with a unique pharmacology, however, evidence for such heterodimers in native cells is equivocal and the consequences of this heterodimerization for signalling remains largely unknown. For μ-opioid receptors at least, dimerization does not seem to be required for signalling [52]. A distinct met-enkephalin receptor lacking structural resemblance to the opioid receptors listed has been identified (OGFR, 9NZT2) and termed an opioid growth factor receptor [104].

endomorphin-1 and endomorphin-2 have been identified as highly selective, putative endogenous agonists for the μ-opioid receptor. At present, however, the mechanisms for endomorphin synthesis in vivo have not been established, and there is no gene identified that encodes for either. Thus, the status of these peptides as endogenous ligands remains unproven.

Two areas of increasing importance in defining opioid receptor function are the presence of functionally relevant single nucleotide polymorphisms in human μ-receptors [67] and the identification of biased signalling by opioid receptor ligands, both agonists and antagonists [6,48]. Despite the identification of biased ligands for the μ receptor, the relevance with respect to physiological and behavioral actions in vivo is not clear [32]. Pathway bias for agonists makes general rank orders of potency and efficacy somewhat obsolete, so these do not appear in the table. As ever, the mechanisms underlying the acute and long term regulation of opiod receptor function are the subject of intense investigation and debate.

The richness of opioid receptor pharmacology has been enhanced with the recent discovery of allosteric modulators of μ and δ receptors, notably the positive allosteric modulators and silent allosteric "antagonists" outlined in [7-8]. Negative allosteric modulation of opioid receptors has been previously suggested [46], whether all compounds are acting at a similar site remains to be established.

In the last decade, several opioid receptors structures have been solved in their inactive and active forms: δ receptor [27-28,35,99]; κ receptor [16-17,99,102]; μ receptor [26,41,51,59,74,78,98-99,110]; NOP [61,89,99]. This effort is of great importance for novel structure-based drug design studies.

* Key recommended reading is highlighted with an asterisk

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Kelly E. (2011) The subtleties of µ-opioid receptor phosphorylation. Br J Pharmacol, 164 (2): 294-7. [PMID:21449916]

Kieffer BL, Evans CJ. (2009) Opioid receptors: from binding sites to visible molecules in vivo. Neuropharmacology, 56 Suppl 1: 205-12. [PMID:18718480]

* Pradhan AA, Befort K, Nozaki C, Gavériaux-Ruff C, Kieffer BL. (2011) The delta opioid receptor: an evolving target for the treatment of brain disorders. Trends Pharmacol Sci, 32 (10): 581-90. [PMID:21925742]

Schröder W, Lambert DG, Ko MC, Koch T. (2014) Functional plasticity of the N/OFQ-NOP receptor system determines analgesic properties of NOP receptor agonists. Br J Pharmacol, 171 (16): 3777-800. [PMID:24762001]

Shippenberg TS. (2009) The dynorphin/kappa opioid receptor system: a new target for the treatment of addiction and affective disorders?. Neuropsychopharmacology, 34 (1): 247. [PMID:19079072]

* Valentino RJ, Volkow ND. (2020) Opioid Research: Past and Future. Mol Pharmacol, 98 (4): 389-391. [PMID:32660966]

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Subcommittee members: Lawrence Toll (Chairperson) Department of Biomedical Sciences Charles E. Schmidt College of Medicine Florida Atlantic University 5353 Parkside Drive Jupiter FL 33458 USA Michael Bruchas Departments of Anesthesiology and Anatomy/Neurobiology Washington University School of Medicine 660 So. Euclid Ave. | Box 8054 St. Louis MO 63110 USA Girolamo Caló Section of Pharmacology Department of Pharmaceutical and Pharmacological Sciences University of Padova Largo Meneghetti, 2 35131 Padova Italy MacDonald J. Christie University of Sydney Department of Pharmacology Sydney NSW 2006 Australia Lakshmi A. Devi Mount Sinai School of Medicine Department of Pharmacology & Biological Chemistry 19-84 Annenberg Building Box 1603 1 Gustae Levy Place New York NY 10029 USA Christopher Evans University of California Los Angeles Neuropsychiatry Institute 760 Westwood Plaza Los Angeles CA 90024-1759 USA Stephen Husbands Department of Pharmacy and Pharmacology University of Bath UK Eamonn Kelly, Prof Professor of Molecular Pharmacology School of Physiology Pharmacology and Neuroscience Faculty of Biomedical Sciences Biomedical Sciences Building University of Bristol Bristol BS8 1TD Mary-Jeanne Kreek The Rockefeller University Lab Biology Addictive Diseases 1230 York Avenue New York NY 10021 USA Lee-Yuan Liu-Chen Temple University School of Medicine Department of Pharmacology 3420 N Broad St Philadelphia PA 19140 USA Dominique Massot Institute des Neuroscience Cellulaire et Integrative Université de Strasbourg 5 rue Blaise Pascal 67084 Strasbourg France Philip S. Portoghese University of Minnesota College of Pharmacy Department of Medicinal Chemistry Health Sciences Unit F 308 Harvard Street Minneapolis MN 55455 USA Stefan Schulz Institute of Pharmacology and Toxicology Jena University Hospital Friedrich-Schiller-University Jena, Germany John R. Traynor Department of Pharmacology University of Michigan 1301 MSRB III Ann Arbor MI 48109-0632 USA Hiroshi Ueda Nagasaki Univ Grad Biomed Sci Div Mol Pharmacol & Neurosci 1-14 Bunkyo-machi Nagasaki 852-8521 Japan Yung H. Wong Department of Biochemistry Hong Kong University of Science and Technology Clear Water Bay Kowloon Hong Kong Nurulain Zaveri Astraea Therapeutics, LLC 320 Logue Avenue Suite 142 Mountain View CA 94043 USA Andreas Zimmer Institute of Molecular Psychiatry University of Bonn Sigmund-Freud-Str. 25 53105 Bonn Germany

Other contributors: Anna Borsodi Hungarian Academy Of Sciences Inst Biochem Biological Research Centre Szeged POB 521 Szeged H-6701 Hungary Charles Chavkin University of Washington Sch Med Department of Pharmacology Box 357280 Seattle WA 98195 USA Olivier Civelli School of Pharmaceutical Sciences and Pharmacy University of California, Irvine Department of Pharmacology Irvine, CA 92697-4625 USA Mark Connor Macquarie University Sydney New South Wales Australia Brian M. Cox (Past chairperson) Uniformed Services University Department of Pharmacology 4301 Jones Bridge Road Bethesda MD 20814-4799 USA Graeme Henderson University of Bristol Department of Pharmacology University Walk Bristol BS8 1TD UK Volker Höllt Otto-von-Guericke University Department of Pharmacology Leipziger Str 44 Magdeburg D-39120 Germany Brigitte Kieffer Institute de Génétique et de Biologie Moléculaire et Cellulaire CNRS/INSERM/ULP Parc d'innovation Rue Laurent Fries BP 10142 Illkirch Cedex 67404 France Ian Kitchen University of Surrey School of Biological Sciences Guildford GU2 5XH UK Davide Malfacini Section of Pharmacology Department of Pharmaceutical and Pharmacological Sciences University of Padova Largo Meneghetti, 2 35131 Padova Italy Jean-Claude Meunier IPBS-CNRS UPR 9062 205 route de Narbonne Toulouse Cedex 4 31077 France Toni S. Shippenberg NIH/NIDA Integrative Neuroscience Section 5500 Nathan Shock Dr Baltimore MD 21224 USA Eric J. Simon New York University School of Medicine Department of Psychiatry & Pharmacology Rm HN609 550 First Ave New York NY 10016 USA