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
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
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.
^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. PMID9500506.
^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. PMID16537798. S2CID21838231.
^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. PMID21444630. S2CID10313748.
^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. PMID16408774.
^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. PMID8035418.
^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. PMID9057856.
^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. PMID16809477.
^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. PMID2832195.
^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. PMID18788723.
^Onali P, Dedoni S, Olianas MC (January 2010). "Direct agonist activity of tricyclic antidepressants at distinct opioid receptor subtypes". The Journal of Pharmacology and Experimental Therapeutics. 332 (1): 255–265. doi:10.1124/jpet.109.159939. PMID19828880. S2CID18893305.
^ abKathmann M, Flau K, Redmer A, Tränkle C, Schlicker E (February 2006). "Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors". Naunyn-Schmiedeberg's Archives of Pharmacology. 372 (5): 354–361. doi:10.1007/s00210-006-0033-x. PMID16489449. S2CID4877869.
^ abcTakayama H, Ishikawa H, Kurihara M, Kitajima M, Aimi N, Ponglux D, et al. (April 2002). "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. doi:10.1021/jm010576e. PMID11960505.
^Whistler JL, Enquist J, Marley A, Fong J, Gladher F, Tsuruda P, et al. (July 2002). "Modulation of postendocytic sorting of G protein-coupled receptors". Science. 297 (5581): 615–620. doi:10.1126/science.1073308. PMID12142540. S2CID1219372.
Further reading
Narita M, Funada M, Suzuki T (January 2001). "Regulations of opioid dependence by opioid receptor types". Pharmacology & Therapeutics. 89 (1): 1–15. doi:10.1016/S0163-7258(00)00099-1. PMID11316510.
Simonin F, Befort K, Gavériaux-Ruff C, Matthes H, Nappey V, Lannes B, et al. (December 1994). "The human delta-opioid receptor: genomic organization, cDNA cloning, functional expression, and distribution in human brain". Molecular Pharmacology. 46 (6): 1015–1021. PMID7808419.
Befort K, Mattéi MG, Roeckel N, Kieffer B (March 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): 143–145. doi:10.1006/geno.1994.1146. PMID8020949.
Knapp RJ, Malatynska E, Fang L, Li X, Babin E, Nguyen M, et al. (1994). "Identification of a human delta opioid receptor: cloning and expression". Life Sciences. 54 (25): PL463–PL469. doi:10.1016/0024-3205(94)90138-4. PMID8201839.
Georgoussi Z, Carr C, Milligan G (July 1993). "Direct measurements of in situ interactions of rat brain opioid receptors with the guanine nucleotide-binding protein Go". Molecular Pharmacology. 44 (1): 62–69. PMID8393523.
Gelernter J, Kranzler HR (July 2000). "Variant detection at the delta opioid receptor (OPRD1) locus and population genetics of a novel variant affecting protein sequence". Human Genetics. 107 (1): 86–88. doi:10.1007/s004390050016. PMID10982041.
Guo J, Wu Y, Zhang W, Zhao J, Devi LA, Pei G, et al. (November 2000). "Identification of G protein-coupled receptor kinase 2 phosphorylation sites responsible for agonist-stimulated delta-opioid receptor phosphorylation". Molecular Pharmacology. 58 (5): 1050–1056. doi:10.1124/mol.58.5.1050. PMID11040053.
Xu W, Chen C, Huang P, Li J, de Riel JK, Javitch JA, et al. (November 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): 13904–13915. doi:10.1021/bi001099p. PMID11076532.
Yeo A, Samways DS, Fowler CE, Gunn-Moore F, Henderson G (March 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): 1688–1700. doi:10.1046/j.1471-4159.2001.00185.x. PMID11259487. S2CID2755275.
External links
"Opioid Receptors: δ". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2014-02-23. Retrieved 2007-07-23.
