Δ-opioid receptor explained

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.[1] 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.[2]

Function

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.[3] [4] 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.[5]

Evidence for whether delta agonists produce respiratory depression is mixed; high doses of the delta agonist peptide DPDPE produced respiratory depression in sheep.[6] 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.[7] 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.[8]

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[9] and also upregulation of BDNF production in the brain in animal models of depression.[10] These antidepressant effects have been linked to endogenous opioid peptides acting at δ- and μ-opioid receptors,[11] and so can also be produced by enkephalinase inhibitors such as RB-101.[12] 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.[13] [14] 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.[15] 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.[16] 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.[17] 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.[18]

Ligands

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,[19] the more potent (+)-BW373U86,[20] a newer drug DPI-287, which does not produce the problems with convulsions seen with the earlier agents,[21] and the mixed μ/δ agonist DPI-3290, which is a much more potent analgesic than the more highly selective δ agonists.[22] Selective antagonists for the δ receptor are also available, with the best known being the opiate derivative naltrindole.[23]

Agonists

Peptides
Non-peptides

Antagonists

Interactions

δ-opioid receptors have been shown to interact with β2 adrenergic receptors,[28] arrestin β1[29] and GPRASP1.[30]

See also

Further reading

External links

Notes and References

  1. Quock RM, Burkey TH, Varga E, Hosohata Y, Hosohata K, Cowell SM, Slate CA, Ehlert FJ, Roeske WR, Yamamura HI . The delta-opioid receptor: molecular pharmacology, signal transduction, and the determination of drug efficacy . Pharmacological Reviews . 51 . 3 . 503–532 . September 1999 . 10471416 .
  2. Peppin JF, Raffa RB . Delta opioid agonists: a concise update on potential therapeutic applications . Journal of Clinical Pharmacy and Therapeutics . 40 . 2 . 155–166 . April 2015 . 25726896 . 10.1111/jcpt.12244 . 25483387 . free .
  3. Varga EV, Navratilova E, Stropova D, Jambrosic J, Roeske WR, Yamamura HI . Agonist-specific regulation of the delta-opioid receptor . Life Sciences . 76 . 6 . 599–612 . December 2004 . 15567186 . 10.1016/j.lfs.2004.07.020 .
  4. [Alvimopan]
  5. Berrocoso E, Sánchez-Blázquez P, Garzón J, Mico JA . Opiates as antidepressants . Current Pharmaceutical Design . 15 . 14 . 1612–1622 . 2009 . 19442177 . 10.2174/138161209788168100 . 10261/62156 .
  6. Clapp JF, Kett A, Olariu N, Omoniyi AT, Wu D, Kim H, Szeto HH . Cardiovascular and metabolic responses to two receptor-selective opioid agonists in pregnant sheep . American Journal of Obstetrics and Gynecology . 178 . 2 . 397–401 . February 1998 . 9500506 . 10.1016/S0002-9378(98)80032-X .
  7. Su YF, McNutt RW, Chang KJ . Delta-opioid ligands reverse alfentanil-induced respiratory depression but not antinociception . The Journal of Pharmacology and Experimental Therapeutics . 287 . 3 . 815–823 . December 1998 . 9864259 .
  8. Jutkiewicz EM, Baladi MG, Folk JE, Rice KC, Woods JH . 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 . June 2006 . 16537798 . 10.1124/jpet.105.095810 . 21838231 .
  9. Broom DC, Jutkiewicz EM, Rice KC, Traynor JR, Woods JH . Behavioral effects of delta-opioid receptor agonists: potential antidepressants? . Japanese Journal of Pharmacology . 90 . 1 . 1–6 . September 2002 . 12396021 . 10.1254/jjp.90.1 . free .
  10. Torregrossa MM, Jutkiewicz EM, Mosberg HI, Balboni G, Watson SJ, Woods JH . Peptidic delta opioid receptor agonists produce antidepressant-like effects in the forced swim test and regulate BDNF mRNA expression in rats . Brain Research . 1069 . 1 . 172–181 . January 2006 . 16364263 . 1780167 . 10.1016/j.brainres.2005.11.005 .
  11. Zhang H, Torregrossa MM, Jutkiewicz EM, Shi YG, Rice KC, Woods JH, Watson SJ, Ko MC . Endogenous opioids upregulate brain-derived neurotrophic factor mRNA through delta- and micro-opioid receptors independent of antidepressant-like effects . The European Journal of Neuroscience . 23 . 4 . 984–994 . February 2006 . 16519663 . 1462954 . 10.1111/j.1460-9568.2006.04621.x .
  12. Jutkiewicz EM, Torregrossa MM, Sobczyk-Kojiro K, Mosberg HI, Folk JE, Rice KC, Watson SJ, Woods JH . Behavioral and neurobiological effects of the enkephalinase inhibitor RB101 relative to its antidepressant effects . European Journal of Pharmacology . 531 . 1–3 . 151–159 . February 2006 . 16442521 . 1828120 . 10.1016/j.ejphar.2005.12.002 .
  13. 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 . Preclinical pharmacology of AZD2327: a highly selective agonist of the δ-opioid receptor . The Journal of Pharmacology and Experimental Therapeutics . 338 . 1 . 195–204 . July 2011 . 21444630 . 10.1124/jpet.111.179432 . 10313748 .
  14. 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. 2015-12-11.
  15. Fan T, Varghese G, Nguyen T, Tse R, O'Dowd BF, George SR . 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 . November 2005 . 16159882 . 10.1074/jbc.M505644200 . 32785318 . free .
  16. Lambert NA, Javitch JA . Rebuttal from Nevin A. Lambert and Jonathan A. Javitch . The Journal of Physiology . 592 . 12 . 2449 . June 2014 . 24931947 . 4080929 . 10.1113/jphysiol.2014.274241 .
  17. Zhang J, Qian H, Zhao P, Hong SS, Xia Y . Rapid hypoxia preconditioning protects cortical neurons from glutamate toxicity through delta-opioid receptor . Stroke . 37 . 4 . 1094–1099 . April 2006 . 16514101 . 10.1161/01.STR.0000206444.29930.18 . 21120257 . free .
  18. Guo L, Zhang L, Zhang DC . [Mechanisms of delta-opioids cardioprotective effects in ischemia and its potential clinical applications] . zh . Sheng Li Ke Xue Jin Zhan [Progress in Physiology] . 36 . 4 . 333–336 . October 2005 . 16408774 .
  19. Calderon SN, Rothman RB, Porreca F, Flippen-Anderson JL, McNutt RW, Xu H, Smith LE, Bilsky EJ, Davis P, Rice KC . 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 . July 1994 . 8035418 . 10.1021/jm00040a002 .
  20. 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 . 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 . February 1997 . 9057856 . 10.1021/jm960319n .
  21. Jutkiewicz EM . The antidepressant -like effects of delta-opioid receptor agonists . Molecular Interventions . 6 . 3 . 162–169 . June 2006 . 16809477 . 10.1124/mi.6.3.7 .
  22. Ananthan S . Opioid ligands with mixed mu/delta opioid receptor interactions: an emerging approach to novel analgesics . The AAPS Journal . 8 . 1 . E118–E125 . March 2006 . 16584118 . 2751430 . 10.1208/aapsj080114 .
  23. Portoghese PS, Sultana M, Takemori AE . Naltrindole, a highly selective and potent non-peptide delta opioid receptor antagonist . European Journal of Pharmacology . 146 . 1 . 185–186 . January 1988 . 2832195 . 10.1016/0014-2999(88)90502-X .
  24. 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 . 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 . October 2008 . 18788723 . 10.1021/jm8008986 .
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  26. Kathmann M, Flau K, Redmer A, Tränkle C, Schlicker E . Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors . Naunyn-Schmiedeberg's Archives of Pharmacology . 372 . 5 . 354–361 . February 2006 . 16489449 . 10.1007/s00210-006-0033-x . 4877869 .
  27. Takayama H, Ishikawa H, Kurihara M, Kitajima M, Aimi N, Ponglux D, Koyama F, Matsumoto K, Moriyama T, Yamamoto LT, Watanabe K, Murayama T, Horie S . Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: discovery of opioid agonists structurally different from other opioid ligands . Journal of Medicinal Chemistry . 45 . 9 . 1949–1956 . April 2002 . 11960505 . 10.1021/jm010576e .
  28. McVey M, Ramsay D, Kellett E, Rees S, Wilson S, Pope AJ, Milligan G . 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 . April 2001 . 11278447 . 10.1074/jbc.M008902200 . 25191463 . free .
  29. Cen B, Yu Q, Guo J, Wu Y, Ling K, Cheng Z, Ma L, Pei G . Direct binding of beta-arrestins to two distinct intracellular domains of the delta opioid receptor . Journal of Neurochemistry . 76 . 6 . 1887–1894 . March 2001 . 11259507 . 10.1046/j.1471-4159.2001.00204.x . 83485138 . free .
  30. Whistler JL, Enquist J, Marley A, Fong J, Gladher F, Tsuruda P, Murray SR, Von Zastrow M . Modulation of postendocytic sorting of G protein-coupled receptors . Science . 297 . 5581 . 615–620 . July 2002 . 12142540 . 10.1126/science.1073308 . 1219372 .

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