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Opioid receptors C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
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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.
Receptors
Targets of relevance to immunopharmacology are highlighted in blue
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δ receptor C
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κ receptor C
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μ receptor C
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NOP receptor C
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Further reading
* Key recommended reading is highlighted with an asterisk
* Butelman ER, Yuferov V, Kreek MJ. (2012) κ-opioid receptor/dynorphin system: genetic and pharmacotherapeutic implications for addiction. Trends Neurosci, 35 (10): 587-96. [PMID:22709632]
Chaudun F, Python L, Liu Y, Hiver A, Cand J, Kieffer BL, Valjent E, Lüscher C. (2024) Distinct µ-opioid ensembles trigger positive and negative fentanyl reinforcement. Nature, 630 (8015): 141-148. [PMID:38778097]
* Cox BM, Christie MJ, Devi L, Toll L, Traynor JR. (2015) Challenges for opioid receptor nomenclature: IUPHAR Review 9. Br J Pharmacol, 172 (2): 317-23. [PMID:24528283]
* Gillis A, Sreenivasan V, Christie MJ. (2020) Intrinsic Efficacy of Opioid Ligands and Its Importance for Apparent Bias, Operational Analysis, and Therapeutic Window. Mol Pharmacol, 98 (4): 410-424. [PMID:32665252]
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]
* Williams JT, Ingram SL, Henderson G, Chavkin C, von Zastrow M, Schulz S, Koch T, Evans CJ, Christie MJ. (2013) Regulation of μ-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol Rev, 65 (1): 223-54. [PMID:23321159]
References
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NC-IUPHAR subcommittee and family contributors
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Michael Bruchas
Girolamo Caló
MacDonald J. Christie
Lakshmi A. Devi
Christopher Evans
Stephen Husbands
Eamonn Kelly, Prof
Mary-Jeanne Kreek
Lee-Yuan Liu-Chen
Dominique Massot
Philip S. Portoghese
Stefan Schulz
John R. Traynor
Hiroshi Ueda
Yung H. Wong
Nurulain Zaveri
Andreas Zimmer |
Other contributors:
Anna Borsodi
Charles Chavkin
Olivier Civelli
Mark Connor
Brian M. Cox (Past chairperson)
Graeme Henderson
Volker Höllt
Brigitte Kieffer
Ian Kitchen
Davide Malfacini
Jean-Claude Meunier
Toni S. Shippenberg
Eric J. Simon |
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Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors. Br J Pharmacol. 180 Suppl 2:S23-S144.
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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.