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δ-opioid receptor

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OPRD1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesOPRD1, OPRD, Δ-opioid receptor, opioid receptor delta 1, DOP, DOR1, DOR
External IDsOMIM: 165195; MGI: 97438; HomoloGene: 20252; GeneCards: OPRD1; OMA:OPRD1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

4985

18386

Ensembl

ENSG00000116329

ENSMUSG00000050511

UniProt

P41143

P32300

RefSeq (mRNA)

NM_000911

NM_013622

RefSeq (protein)

NP_000902

NP_038650

Location (UCSC)Chr 1: 28.81 – 28.87 MbChr 4: 131.84 – 131.87 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi/G0 and has enkephalins as its endogenous ligands.[5] 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.[6]

Function

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The endogenous system of opioid receptors is well known for its analgesic potential; however, the exact role of δ-opioid receptor activation in pain modulation is largely up for debate. This also depends on the model at hand since receptor activity is known to change from species to species. Activation of delta receptors produces analgesia, perhaps as significant potentiators of μ-opioid receptor agonists. However, it seems like delta agonism provides heavy potentiation to any mu agonism. Therefore, even selective mu agonists can cause analgesia under the right conditions, whereas under others can cause none whatsoever.[7][8] It is also suggested however that the pain modulated by the μ-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.[9]

Evidence for whether delta agonists produce respiratory depression is mixed; high doses of the delta agonist peptide DPDPE produced respiratory depression in sheep.[10] In contrast both the peptide delta agonist Deltorphin II and the non-peptide delta agonist (+)-BW373U86 actually stimulated respiratory function and blocked the respiratory depressant effect of the potent μ-opioid agonist alfentanil, without affecting pain relief.[11] 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 mu/delta agonists such as DPI-3290 potentially very useful drugs that might be much safer than the μ agonists currently used for pain relief. Many delta agonists may also cause seizures at high doses, although not all delta agonists produce this effect.[12]

Of additional interest is the potential for delta agonists to be developed for use as a novel class of antidepressant drugs, following robust evidence of both antidepressant effects[13] and also upregulation of BDNF production in the brain in animal models of depression.[14] These antidepressant effects have been linked to endogenous opioid peptides acting at δ- and μ-opioid receptors,[15] and so can also be produced by enkephalinase inhibitors such as RB-101.[16] 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 δ-opioid receptor 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.[17][18] Further trials are required.

Another interesting aspect of δ-opioid receptor function is the suggestion of μ/δ-opioid receptor interactions. At the extremes of this suggestion lies the possibility of a μ/δ 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.[19] 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.[20] 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 delta receptors mimic the phenomenon known as ischemic preconditioning.[21] 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 DOR activity mimic this effect. In the rat model, introduction of DOR ligands results in significant cardioprotection.[22]

Ligands

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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 receptor agonists available, including peptides such as DPDPE and deltorphin II, and non-peptide drugs such as SNC-80,[23] the more potent (+)-BW373U86,[24] a newer drug DPI-287, which does not produce the problems with convulsions seen with the earlier agents,[25] and the mixed μ/δ agonist DPI-3290, which is a much more potent analgesic than the more highly selective δ agonists.[26] Selective antagonists for the δ receptor are also available, with the best known being the opiate derivative naltrindole.[27]

Agonists

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A showing of selective delta opioid ligands. Blue represents a common phenolic moiety, yellow a basic nitrogen, and red a diethyl amide moiety which is not set in stone, but rather a bulky region that fits into a hydrophobic pocket.
Peptides
Non-peptides

Antagonists

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Interactions

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δ-opioid receptors have been shown to interact with β2 adrenergic receptors,[32] arrestin β1[33] and GPRASP1.[34]

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000116329 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000050511 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Quock RM, Burkey TH, Varga E, Hosohata Y, Hosohata K, Cowell SM, et al. (September 1999). "The delta-opioid receptor: molecular pharmacology, signal transduction, and the determination of drug efficacy". Pharmacological Reviews. 51 (3): 503–532. PMID 10471416.
  6. ^ Peppin JF, Raffa RB (April 2015). "Delta opioid agonists: a concise update on potential therapeutic applications". Journal of Clinical Pharmacy and Therapeutics. 40 (2): 155–166. doi:10.1111/jcpt.12244. PMID 25726896. S2CID 25483387.
  7. ^ Varga EV, Navratilova E, Stropova D, Jambrosic J, Roeske WR, Yamamura HI (December 2004). "Agonist-specific regulation of the delta-opioid receptor". Life Sciences. 76 (6): 599–612. doi:10.1016/j.lfs.2004.07.020. PMID 15567186.
  8. ^ Alvimopan
  9. ^ Berrocoso E, Sánchez-Blázquez P, Garzón J, Mico JA (2009). "Opiates as antidepressants". Current Pharmaceutical Design. 15 (14): 1612–1622. doi:10.2174/138161209788168100. hdl:10261/62156. PMID 19442177.
  10. ^ Clapp JF, Kett A, Olariu N, Omoniyi AT, Wu D, Kim H, et al. (February 1998). "Cardiovascular and metabolic responses to two receptor-selective opioid agonists in pregnant sheep". American Journal of Obstetrics and Gynecology. 178 (2): 397–401. doi:10.1016/S0002-9378(98)80032-X. PMID 9500506.
  11. ^ Su YF, McNutt RW, Chang KJ (December 1998). "Delta-opioid ligands reverse alfentanil-induced respiratory depression but not antinociception". The Journal of Pharmacology and Experimental Therapeutics. 287 (3): 815–823. PMID 9864259.
  12. ^ Jutkiewicz EM, Baladi MG, Folk JE, Rice KC, Woods JH (June 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): 1337–1348. doi:10.1124/jpet.105.095810. PMID 16537798. S2CID 21838231.
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  16. ^ Jutkiewicz EM, Torregrossa MM, Sobczyk-Kojiro K, Mosberg HI, Folk JE, Rice KC, et al. (February 2006). "Behavioral and neurobiological effects of the enkephalinase inhibitor RB101 relative to its antidepressant effects". European Journal of Pharmacology. 531 (1–3): 151–159. doi:10.1016/j.ejphar.2005.12.002. PMC 1828120. PMID 16442521.
  17. ^ Hudzik TJ, Maciag C, Smith MA, Caccese R, Pietras MR, Bui KH, et al. (July 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. PMID 21444630. S2CID 10313748.
  18. ^ "Study of Antidepressant Efficacy of a Selective, High Affinity Enkephalinergic Agonist in Anxious Major Depressive Disorder (AMDD) - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. 10 October 2012. Retrieved 2015-12-11.
  19. ^ Fan T, Varghese G, Nguyen T, Tse R, O'Dowd BF, George SR (November 2005). "A role for the distal carboxyl tails in generating the novel pharmacology and G protein activation profile of mu and delta opioid receptor hetero-oligomers". The Journal of Biological Chemistry. 280 (46): 38478–38488. doi:10.1074/jbc.M505644200. PMID 16159882. S2CID 32785318.
  20. ^ Lambert NA, Javitch JA (June 2014). "Rebuttal from Nevin A. Lambert and Jonathan A. Javitch". The Journal of Physiology. 592 (12): 2449. doi:10.1113/jphysiol.2014.274241. PMC 4080929. PMID 24931947.
  21. ^ Zhang J, Qian H, Zhao P, Hong SS, Xia Y (April 2006). "Rapid hypoxia preconditioning protects cortical neurons from glutamate toxicity through delta-opioid receptor". Stroke. 37 (4): 1094–1099. doi:10.1161/01.STR.0000206444.29930.18. PMID 16514101. S2CID 21120257.
  22. ^ Guo L, Zhang L, Zhang DC (October 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): 333–336. PMID 16408774.
  23. ^ Calderon SN, Rothman RB, Porreca F, Flippen-Anderson JL, McNutt RW, Xu H, et al. (July 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): 2125–2128. doi:10.1021/jm00040a002. PMID 8035418.
  24. ^ Calderon SN, Rice KC, Rothman RB, Porreca F, Flippen-Anderson JL, Kayakiri H, et al. (February 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. PMID 9057856.
  25. ^ Jutkiewicz EM (June 2006). "The antidepressant -like effects of delta-opioid receptor agonists". Molecular Interventions. 6 (3): 162–169. doi:10.1124/mi.6.3.7. PMID 16809477.
  26. ^ Ananthan S (March 2006). "Opioid ligands with mixed mu/delta opioid receptor interactions: an emerging approach to novel analgesics". The AAPS Journal. 8 (1): E118–E125. doi:10.1208/aapsj080114. PMC 2751430. PMID 16584118.
  27. ^ Portoghese PS, Sultana M, Takemori AE (January 1988). "Naltrindole, a highly selective and potent non-peptide delta opioid receptor antagonist". European Journal of Pharmacology. 146 (1): 185–186. doi:10.1016/0014-2999(88)90502-X. PMID 2832195.
  28. ^ Le Bourdonnec B, Windh RT, Ajello CW, Leister LK, Gu M, Chu GH, et al. (October 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): 5893–5896. doi:10.1021/jm8008986. PMID 18788723.
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  32. ^ McVey M, Ramsay D, Kellett E, Rees S, Wilson S, Pope AJ, et al. (April 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): 14092–14099. doi:10.1074/jbc.M008902200. PMID 11278447. S2CID 25191463.
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Further reading

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