The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G proteinGi/G0 and has enkephalins as its endogenous ligands. The regions of the brain where the δ-opioid receptor is largely expressed vary from species model to species model. In humans, the δ-opioid receptor is most heavily expressed in the basal ganglia and neocortical regions of the brain; the basal ganglia, which is heavily GABA populated, has been linked to major depressive disorder, suggesting a possible role for the δ-opioid receptor in mood modulation.
The endogenous system of opioid receptors (μ MOR,κ KOR, and, δ DOR) is well known for its analgesic potential; however, the exact role of δ-opioid receptor activation in pain modulation is largely up for debate. Largely this also depends on the model at hand since receptor activity is known to change from species to species. Activation of δ receptors produces analgesia, perhaps as significant potentiators of mu-opioid agonists.[clarification needed] However, it seems like delta agonism provides heavy potentiation to any MOR agonism. Therefore, even selective mu agonists can cause analgesia under the right conditions, whereas others can cause none whatsoever. It is also suggested however that the pain modulated by the mu-opioid receptor and that modulated by the δ-opioid receptor are distinct types, with the assertion that DOR modulates the nociception of chronic pain, while MOR modulates acute pain.
Evidence for whether δ agonists produce respiratory depression is mixed; high doses of the δ agonist peptide DPDPE produced respiratory depression in sheep, but in tests on mice the non-peptide δ agonist SNC-80 produced respiratory depression only at the very high dose of 40 mg/kg. In contrast both the peptide δ agonist Deltorphin II and the non-peptide δ agonist (+)-BW373U86 actually stimulated respiratory function and blocked the respiratory depressant effect of the potent μ-opioid agonist alfentanil, without affecting pain relief. It thus seems likely that while δ opioid agonists can produce respiratory depression at very high doses, at lower doses they have the opposite effect, a fact that may make mixed μ/δ agonists such as DPI-3290 potentially very useful drugs that might be much safer than the μ agonists currently used for pain relief.Many δ agonists may also cause seizures at high doses, although not all δ agonists produce this effect.
Of additional interest is the potential for δ agonists to be developed for use as a novel class of antidepressant drugs, following robust evidence of both antidepressant effects and also upregulation of BDNF production in the brain in animal models of depression. These antidepressant effects have been linked to endogenous opioid peptides acting at δ and μ opioid receptors, and so can also be produced by enkephalinase inhibitors such as RB-101. ] However, in human models the data for antidepressant effects remains inconclusive. In the 2008 Phase 2 clinical trial by Astra Zeneca, NCT00759395, 15 patients were treated with the selective delta agonist AZD 2327. The results showed no significant effect on mood suggesting that delta modulation might not participate in the regulation of mood in humans. However, doses were administered at low doses and the pharmacological data also remains inconclusive. Further trials are required.
Another interesting aspect of δ-opioid receptor function is the suggestion of mu/delta opioid receptor interactions. At the extremes of this suggestion lies the possibility of a mu-delta opioid receptor oligomer. The evidence for this stems from the different binding profiles of typical mu and delta agonists such as morphine and DAMGO respectively, in cells that coexpress both receptors compared to those in cells that express them individually. In addition, work by Fan and coworkers shows the restoration of the binding profiles when distal carboxyl termini are truncated at either receptor, suggesting that the termini play a role in the oligomerization. While this is exciting, rebuttal by the Javitch and coworkers suggest the idea of oligomerization may be overplayed. Relying on RET, Javitch and coworkers showed that RET signals were more characteristic of random proximity between receptors, rather than an actual bond formation between receptors, suggesting that discrepancies in binding profiles may be the result of downstream interactions, rather than novel effects due to oligomerization. Nevertheless, coexpression of receptors remains unique and potentially useful in the treatment of mood disorders and pain.
Recent work indicates that exogenous ligands that activate the δ receptors mimic the phenomenon known as ischemic preconditioning. Experimentally, if short periods of transient ischemia are induced the downstream tissues are robustly protected if longer-duration interruption of the blood supply is then affected. Opiates and opioids with δ activity mimic this effect. In the rat model, introduction of δ active ligands results in significant cardioprotection.
Until comparatively recently, there were few pharmacological tools for the study of δ receptors. As a consequence, our understanding of their function is much more limited than those of the other opioid receptors for which selective ligands have long been available.
However, there are now several selective δ opioid agonists available, including peptides such as DPDPE and deltorphin II, and non-peptide drugs such as SNC-80, the more potent (+)-BW373U86, a newer drug DPI-287, which does not produce the problems with convulsions seen with the earlier agents, and the mixed μ/δ agonist DPI-3290, which is a much more potent analgesic than the more highly selective δ agonists. Selective antagonists for the δ receptor are also available, with the best known being the opiate derivative naltrindole.
A showing of selective delta opioid ligands. Blue represents a common phenolic moiety, yellow a basic nitrogen, and red a diethyl amide moiety which isn't set in stone, but rather a bulky region that fits into a hydrophobic pocket.
^Gallantine EL, Meert TF (Jul 2005). "A comparison of the antinociceptive and adverse effects of the mu-opioid agonist morphine and the delta-opioid agonist SNC80". Basic & Clinical Pharmacology & Toxicology. 97 (1): 39–51. doi:10.1111/j.1742-7843.2005.pto_07.x. PMID15943758.
^Jutkiewicz EM, Baladi MG, Folk JE, Rice KC, Woods JH (Jun 2006). "The convulsive and electroencephalographic changes produced by nonpeptidic delta-opioid agonists in rats: comparison with pentylenetetrazol". The Journal of Pharmacology and Experimental Therapeutics. 317 (3): 1337–48. doi:10.1124/jpet.105.095810. PMID16537798.
^Broom DC, Jutkiewicz EM, Rice KC, Traynor JR, Woods JH (Sep 2002). "Behavioral effects of delta-opioid receptor agonists: potential antidepressants?". Japanese Journal of Pharmacology. 90 (1): 1–6. doi:10.1254/jjp.90.1. PMID12396021.
^Hudzik TJ, Maciag C, Smith MA, Caccese R, Pietras MR, Bui KH, Coupal M, Adam L, Payza K, Griffin A, Smagin G, Song D, Swedberg MD, Brown W (Jul 2011). "Preclinical pharmacology of AZD2327: a highly selective agonist of the δ-opioid receptor". The Journal of Pharmacology and Experimental Therapeutics. 338 (1): 195–204. doi:10.1124/jpet.111.179432. PMID21444630.
^Lambert, Nevin A; Javitch, Jonathan A (2014). "Rebuttal from Nevin A. Lambert and Jonathan A. Javitch". The Journal of Physiology. doi:10.1113/jphysiol.2014.274241.
^Zhang J, Qian H, Zhao P, Hong SS, Xia Y (Apr 2006). "Rapid hypoxia preconditioning protects cortical neurons from glutamate toxicity through delta-opioid receptor". Stroke: A Journal of Cerebral Circulation. 37 (4): 1094–9. doi:10.1161/01.STR.0000206444.29930.18. PMID16514101.
^Guo L, Zhang L, Zhang DC (Oct 2005). "[Mechanisms of delta-opioids cardioprotective effects in ischemia and its potential clinical applications]". Sheng Li Ke Xue Jin Zhan [Progress in Physiology] (in Chinese). 36 (4): 333–6. PMID16408774.
^Calderon SN, Rothman RB, Porreca F, Flippen-Anderson JL, McNutt RW, Xu H, Smith LE, Bilsky EJ, Davis P, Rice KC (Jul 1994). "Probes for narcotic receptor mediated phenomena. 19. Synthesis of (+)-4-[(alpha R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3- methoxybenzyl]-N,N-diethylbenzamide (SNC 80): a highly selective, nonpeptide delta opioid receptor agonist". Journal of Medicinal Chemistry. 37 (14): 2125–8. doi:10.1021/jm00040a002. PMID8035418.
^Calderon SN, Rice KC, Rothman RB, Porreca F, Flippen-Anderson JL, Kayakiri H, Xu H, Becketts K, Smith LE, Bilsky EJ, Davis P, Horvath R (Feb 1997). "Probes for narcotic receptor mediated phenomena. 23. Synthesis, opioid receptor binding, and bioassay of the highly selective delta agonist (+)-4-[(alpha R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]- N,N-diethylbenzamide (SNC 80) and related novel nonpeptide delta opioid receptor ligands". Journal of Medicinal Chemistry. 40 (5): 695–704. doi:10.1021/jm960319n. PMID9057856.
^Jutkiewicz EM (Jun 2006). "The antidepressant -like effects of delta-opioid receptor agonists". Molecular Interventions. 6 (3): 162–9. doi:10.1124/mi.6.3.7. PMID16809477.
^Portoghese PS, Sultana M, Takemori AE (Jan 1988). "Naltrindole, a highly selective and potent non-peptide delta opioid receptor antagonist". European Journal of Pharmacology. 146 (1): 185–6. doi:10.1016/0014-2999(88)90502-X. PMID2832195.
^Le Bourdonnec B, Windh RT, Ajello CW, Leister LK, Gu M, Chu GH, Tuthill PA, Barker WM, Koblish M, Wiant DD, Graczyk TM, Belanger S, Cassel JA, Feschenko MS, Brogdon BL, Smith SA, Christ DD, Derelanko MJ, Kutz S, Little PJ, DeHaven RN, DeHaven-Hudkins DL, Dolle RE (Oct 2008). "Potent, orally bioavailable delta opioid receptor agonists for the treatment of pain: discovery of N,N-diethyl-4-(5-hydroxyspiro[chromene-2,4'-piperidine]-4-yl)benzamide (ADL5859)". Journal of Medicinal Chemistry. 51 (19): 5893–6. doi:10.1021/jm8008986. PMID18788723.
^ abKathmann M, Flau K, Redmer A, Tränkle C, Schlicker E (Feb 2006). "Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors". Naunyn-Schmiedeberg's Archives of Pharmacology. 372 (5): 354–61. doi:10.1007/s00210-006-0033-x. PMID16489449.
^McVey M, Ramsay D, Kellett E, Rees S, Wilson S, Pope AJ, Milligan G (Apr 2001). "Monitoring receptor oligomerization using time-resolved fluorescence resonance energy transfer and bioluminescence resonance energy transfer. The human delta -opioid receptor displays constitutive oligomerization at the cell surface, which is not regulated by receptor occupancy". The Journal of Biological Chemistry. 276 (17): 14092–9. doi:10.1074/jbc.M008902200. PMID11278447.
^Cen B, Yu Q, Guo J, Wu Y, Ling K, Cheng Z, Ma L, Pei G (Mar 2001). "Direct binding of beta-arrestins to two distinct intracellular domains of the delta opioid receptor". Journal of Neurochemistry. 76 (6): 1887–94. doi:10.1046/j.1471-4159.2001.00204.x. PMID11259507.
^Whistler JL, Enquist J, Marley A, Fong J, Gladher F, Tsuruda P, Murray SR, Von Zastrow M (Jul 2002). "Modulation of postendocytic sorting of G protein-coupled receptors". Science. 297 (5581): 615–20. doi:10.1126/science.1073308. PMID12142540.
Evans CJ, Keith DE, Morrison H, Magendzo K, Edwards RH (Dec 1992). "Cloning of a delta opioid receptor by functional expression". Science. 258 (5090): 1952–5. doi:10.1126/science.1335167. PMID1335167.
Offermanns S, Schultz G, Rosenthal W (Feb 1991). "Evidence for opioid receptor-mediated activation of the G-proteins, Go and Gi2, in membranes of neuroblastoma x glioma (NG108-15) hybrid cells". The Journal of Biological Chemistry. 266 (6): 3365–8. PMID1671672.
Simonin F, Befort K, Gavériaux-Ruff C, Matthes H, Nappey V, Lannes B, Micheletti G, Kieffer B (Dec 1994). "The human delta-opioid receptor: genomic organization, cDNA cloning, functional expression, and distribution in human brain". Molecular Pharmacology. 46 (6): 1015–21. PMID7808419.
Befort K, Mattéi MG, Roeckel N, Kieffer B (Mar 1994). "Chromosomal localization of the delta opioid receptor gene to human 1p34.3-p36.1 and mouse 4D bands by in situ hybridization". Genomics. 20 (1): 143–5. doi:10.1006/geno.1994.1146. PMID8020949.
Knapp RJ, Malatynska E, Fang L, Li X, Babin E, Nguyen M, Santoro G, Varga EV, Hruby VJ, Roeske WR (1994). "Identification of a human delta opioid receptor: cloning and expression". Life Sciences. 54 (25): PL463–9. doi:10.1016/0024-3205(94)90138-4. PMID8201839.
Georgoussi Z, Carr C, Milligan G (Jul 1993). "Direct measurements of in situ interactions of rat brain opioid receptors with the guanine nucleotide-binding protein Go". Molecular Pharmacology. 44 (1): 62–9. PMID8393523.
Hedin KE, Bell MP, Kalli KR, Huntoon CJ, Sharp BM, McKean DJ (Dec 1997). "Delta-opioid receptors expressed by Jurkat T cells enhance IL-2 secretion by increasing AP-1 complexes and activity of the NF-AT/AP-1-binding promoter element". Journal of Immunology. 159 (11): 5431–40. PMID9548483.
Petaja-Repo UE, Hogue M, Laperriere A, Walker P, Bouvier M (May 2000). "Export from the endoplasmic reticulum represents the limiting step in the maturation and cell surface expression of the human delta opioid receptor". The Journal of Biological Chemistry. 275 (18): 13727–36. doi:10.1074/jbc.275.18.13727. PMID10788493.
Gelernter J, Kranzler HR (Jul 2000). "Variant detection at the delta opioid receptor (OPRD1) locus and population genetics of a novel variant affecting protein sequence". Human Genetics. 107 (1): 86–8. doi:10.1007/s004390050016. PMID10982041.
Guo J, Wu Y, Zhang W, Zhao J, Devi LA, Pei G, Ma L (Nov 2000). "Identification of G protein-coupled receptor kinase 2 phosphorylation sites responsible for agonist-stimulated delta-opioid receptor phosphorylation". Molecular Pharmacology. 58 (5): 1050–6. PMID11040053.
Gomes I, Jordan BA, Gupta A, Trapaidze N, Nagy V, Devi LA (Nov 2000). "Heterodimerization of mu and delta opioid receptors: A role in opiate synergy". The Journal of Neuroscience. 20 (22): RC110. PMID11069979.
Xu W, Chen C, Huang P, Li J, de Riel JK, Javitch JA, Liu-Chen LY (Nov 2000). "The conserved cysteine 7.38 residue is differentially accessible in the binding-site crevices of the mu, delta, and kappa opioid receptors". Biochemistry. 39 (45): 13904–15. doi:10.1021/bi001099p. PMID11076532.
Saeed RW, Stefano GB, Murga JD, Short TW, Qi F, Bilfinger TV, Magazine HI (Dec 2000). "Expression of functional delta opioid receptors in vascular smooth muscle". International Journal of Molecular Medicine. 6 (6): 673–7. doi:10.3892/ijmm.6.6.673. PMID11078827.
Xiang B, Yu GH, Guo J, Chen L, Hu W, Pei G, Ma L (Feb 2001). "Heterologous activation of protein kinase C stimulates phosphorylation of delta-opioid receptor at serine 344, resulting in beta-arrestin- and clathrin-mediated receptor internalization". The Journal of Biological Chemistry. 276 (7): 4709–16. doi:10.1074/jbc.M006187200. PMID11085981.
Yeo A, Samways DS, Fowler CE, Gunn-Moore F, Henderson G (Mar 2001). "Coincident signalling between the Gi/Go-coupled delta-opioid receptor and the Gq-coupled m3 muscarinic receptor at the level of intracellular free calcium in SH-SY5Y cells". Journal of Neurochemistry. 76 (6): 1688–700. doi:10.1046/j.1471-4159.2001.00185.x. PMID11259487.