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. 2009 Nov;158(Suppl 1):S78. doi: 10.1111/j.1476-5381.2009.00501_49.x

Opioid and opioid-like

PMCID: PMC2884586

Overview: Opioid and opioid-like receptors are activated by a variety of endogenous peptides including [Met]enkephalin (met), [Leu]enkephalin (leu), β-endorphin (β-end), α-neo-dynorphin, dynorphin A (dynA), dynorphin B (dynB), Big dynorphin (Big dyn), nociceptin/orphanin FQ (N/OFQ) and endomorphin-1 and 2. The Greek letter names for the opioid receptors, µ, δ and κ, are well established, and IUPHAR considers these names most appropriate (Foord et al., 2005). The human N/OFQ receptor is considered ‘opioid-related’ rather than opioid because while it exhibits a high degree of structural homology with the conventional opioid receptors (Mollereau et al., 1994), it displays a distinct pharmacology.

Nomenclature Delta opioid receptor Kappa opioid receptor Mu opioid receptor N/OFQ receptor
Preferred abbreviation δ κ µ NOP
Other names OP1, DOP, DOR OP2, KOP, KOR OP3, MOP, MOR ORL1, OP4
Ensembl ID ENSG00000116329 ENSG00000082556 ENSG00000112038 ENSG00000125510
Principal transduction Gi/o Gi/o Gi/o Gi/o
Rank order of potency β-End = leu = met > dynA Big dyn > dynA >> β-end > leu > met β-End > dynA > met = leu N/OFQ >> dynA
Selective agonists DPDPE (Mosberg et al., 1983), DSBULET (Delay-Goyet et al., 1988), [DAla2]deltorphin I or II (Erspamer et al., 1989), SNC80 (Bilsky et al., 1995) U69593 (Lahti et al., 1985), CI977 (Hunter et al., 1990), Salvinorin A (Roth et al., 2002) Endomorphin-1 and 2 (Zadina et al., 1997), morphine (Goldstein and Naidu, 1989), DAMGO (Handa et al., 1981), sufentanil (Yeadon and Kitchen, 1988), PL017 (Costa et al., 1992) N/OFQ, N/OFQ-(1-13)-NH2 (Guerrini et al., 1997), Ro646198 (Jenck et al., 2000), UFP112 (Rizzi et al., 2007)
Selective antagonists Naltrindole (Portoghese et al., 1988), naltriben (Sofuoglu et al., 1991) Nor-binaltorphimine (Portoghese et al., 1987), GNTI (Stevens et al., 2000) CTAP (Pelton et al., 1986) J113397 (8.3, Kawamoto et al., 1999), SB612111 (8.5, Zaratin et al., 2004), UFP101 (7.2, Calo' et al., 2002)
Probes [3H]-DPDPE (Goldstein and Naidu, 1989), [3H]-naltrindole (Yamamura et al., 1992), [3H]-deltorphin II (Gomes et al., 2000), [3H]-naltriben (Lever and Scheffel, 1998) [3H]-U69593 (Lahti et al., 1985), [3H]-CI977 (Simonin et al., 2001) [3H]-DAMGO (Goldstein and Naidu, 1989), [3H]-PL017 (Hawkins et al., 1987) [3H]-N/OFQ (Dooley and Houghten, 1996), [3H]-Leu-N/OFQ, [125I]-Tyr14-N/OFQ
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Subtypes of µ (µ1, µ2), δ (δ1, δ2) and κ (κ1, κ2, κ3) receptor have been proposed based primarily on binding studies with poorly selective ligands or results from in vivo studies. Only three naloxone-sensitive opioid receptors have been cloned, and while the µ receptor in particular may be subject to extensive alternative splicing, these putative isforms have not been definitively correlated with any of the proposed subtypes. Opioid receptor subtypes may reflect hetero-dimerization of opioid receptors with each other or with other 7TM receptors (Jordan and Devi, 1999), but evidence for heterodimers in native cells is equivocal. A distinct met-enkephalin receptor lacking structural resemblence to the opioid receptors listed has been identified (ENSG00000060491) and termed an opioid growth factor receptor (see Zagon et al., 2002).

Two areas of increasing importance in defining opioid receptor function are the presence of functionally relevant single nucleotide polymorphisms in human µ receptors (see Oertel et al., 2009) and the identification of biased signalling by opioid receptor ligands, in particular, compounds previously characterized as antagonists (Bruchas et al., 2007).

Glossary

Abbreviations:

CI977

(5r)-(5α,7α,8β)-(–)-N-methyl-N-(7-[1-pyrrolidinyl]-1-oxaspiro[4,5]dec-8-yl)-4-benzofuranacetamide hydrochloride

CTAP

D-Phe-cyc[Cys-Tyr-D-Trp-Arg-Thr-Pen]-Thr-NH2

DAMGO

Tyr-DAla-Gly-[NMePhe]-NH(CH2)2

DPDPE

cyc[DPen2, DPen5]enkephalin

DSBULET

Tyr-DSer(OtBu)-Gly-Phe-Leu-Thr

GNTI

5′-guanidinyl-17-(cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-6,7-2′,3′-indolomorphinan

ICI174864

N,N-diallyl-Tyr-Aib-Phe-Leu-OH (Aib is aminoisobutyric acid)

J113397

1-[(3r,4r)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one

PL017

[N-MePhe3,DPro4]morphiceptin

Ro646198

(1S,3aS)-8-(2,3,3a,4.5.6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one

SB612111

(−)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol

SNC80

(+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide

U69593

5α,7α,8β-(−)-N-methyl-N-(7-[1-pyrrolidinyl]-1-oxasipro(4,5)dec-8-yl)benzene acetamide

UFP101

[Nphe1,Arg14,Lys15]nociceptin-NH2

UFP112

[(pF)Phe4Aib7Arg14Lys15]N/OFQ-NH2

Further Reading

Bailey CP, Connor M (2005). Opioids: cellular mechanisms of tolerance and physical dependence. Curr Opin Pharmacol5: 60–68.

Ballantyne JC, Laforge KS (2007). Opioid dependence and addiction during opioid treatment of chronic pain. Pain129: 235–255.

Cahill CM, Holdridge SV, Morinville A (2007). Trafficking of δ-opioid receptors and other G-protein-coupled receptors: implications for pain and analgesia. Trends Pharmacol Sci28: 23–31.

DeHaven-Hudkins DL, DeHaven RN, Little PJ, Techner LM (2008). The involvement of the µ-opioid receptor in gastrointestinal pathophysiology: therapeutic opportunities for antagonism at this receptor. Pharmacol Ther117: 162–187.

Fichna J, Janecka A, Costentin J, Do Rego JC (2007). The endomorphin system and its evolving neurophysiological role. Pharmacol Rev59: 88–123.

Henriksen G, Willoch F (2008). Imaging of opioid receptors in the central nervous system. Brain131: 1171–1196.

Kieffer BL, Evans CJ (2009). Opioid receptors: from binding sites to visible molecules in vivo. Neuropharmacology56 (Suppl. 1): 205–212.

Koch T, Hollt V (2008). Role of receptor internalization in opioid tolerance and dependence. Pharmacol Ther117: 199–206.

Kuszak AJ, Pitchiaya S, Anand JP, Mosberg HI, Walter NG, Sunahara RK (2009). Purification and functional reconstitution of monomeric µ-opioid receptors: allosteric modulation of agonist binding by Gi2. J Biol Chem284: 26732–26741.

Lambert DG (2008). The nociceptin/orphanin FQ receptor: a target with broad therapeutic potential. Nat Rev Drug Discov7: 694–710.

Oertel BG, Kettner M, Scholich K, Renne C, Roskam B, Geisslinger G et al. (2009). A common human micro-opioid receptor genetic variant diminishes the receptor signaling efficacy in brain regions processing the sensory information of pain. J Biol Chem284: 6530–6535.

Pineyro G, Archer-Lahlou E (2007). Ligand-specific receptor states: implications for opiate receptor signalling and regulation. Cell Signal19: 8–19.

Sadee W, Wang D, Bilsky EJ (2005). Basal opioid receptor activity, neutral antagonists, and therapeutic opportunities. Life Sci76: 1427–1437.

Somogyi AA, Barratt DT, Coller JK (2007). Pharmacogenetics of opioids. Clin Pharmacol Ther81: 429–444.

Wang Y, Van Bockstaele EJ, Liu-Chen LY (2008). In vivo trafficking of endogenous opioid receptors. Life Sci83: 693–699.

Zollner C, Stein C (2007). Opioids. Handb Exp Pharmacol177: 31–63.

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