Delta/// agonists

P.L. Wood, S.E. Charleson, D. Lane and R.L. Hudgin, Multiple opiate receptors differential binding of mu, kappa and delta agonists. Neuropharmacology, 20 (1981) 1215-1220. 

Naloxone precipitates nicotine withdrawal in mice Naloxone induces place aversion in nicotine-dependent rats Naloxone prevents nicotine alleviation of nic. withdrawal Mu and delta agonists reduced mec-precipitated aversion Kappa antagonist suppresses mec.-precipitated aversion P-Endorphin metabolite Gly-Glu blocks aversiveness of mec-precipitated withdrawal Mec precipitates hyperalgesia in nicotine-tolerant rats NAcc Met-enkephalin increased Striatum preproenkephalin mRNA increased... 

Polak, P. E., Kalinin, S., Dello Russo, C., Gavrilyuk, V., Sharp, A., Peters, J. M., Richardson, J., Willson, T. M., Weinberg, G., and Feinstein, D. L. (2005). Protective effects of a peroxisome proliferator-activated receptor-beta/delta agonist in experimental autoimmune encephalomyelitis. J. Neuroimmunol. 168, 65—75. 

Many of the areas found to be high in delta receptors are part of the limbic system associated with the control of emotion and reward behavior. Such areas include olfactory tubercle, the nucleus accumbens, and the amygdala. However, recent demonstrations have shown that delta agonists may have antidepression activity in the forced swimming test [24 Chap. 20], and the lack of abuse or self-administrative activity in monkeys [25 Chap. 23] may point to the unknown functions of delta receptors in the limbic system. 

In 1984, Cotton and colleagues described ICI174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH) as a highly selective antagonist for the delta receptors [34]. This peptide was later discovered by Hertz and colleagues [35,36] to be the first inverse delta agonist. 

The selectivity of currently used delta agonists may not be sufficient to avoid mu receptor activation in vivo. As an example, one study showed that DPDPE (selectivity delta/mu 100-fold) injected either ICV or ITH was less active in the mu receptor mutant than deltorphin (selectivity mu/delta 10,000-fold) [60]. This suggests that, in WT mice the less delta selective compound recruits mu receptors to produce analgesia in the tail flick and hot plate tests under their experimental conditions. 

Delta receptors nevertheless mediate some delta agonist induced analgesia, as suggested by reduced DPDPE and deltorphin activity in the DOR mutant after ITH applications [52], or enhanced antinociceptive activity in MOR mutants subjected to CFA inflammation [65]. Delta receptors also depress respiratory neurons in slice preparations [66] and mediate SNC80-evoked convulsions [67]. 

Beyond delta agonist selectivity and mu or delta receptor availability in vivo, the observation of decreased delta agonist efficacy in mice lacking mu receptors could also be explained by functional cooperation of mu and delta receptors. It is likely that some delta receptor-mediated effects require mu receptors for full activity (see Rothman and Xu, Chap. 21). Where in the brain, and whether this occurs between receptors located in the same neurons or on different neurons within neural circuits, remains to be determined. 

In conclusion, the in vivo activity of available delta opioids is complex. DPDPE, or even Delt, administered ICV seems to recruit mu receptors and, from all the data, it appears that delta agonists often have mixed mu/ delta activities. More selective delta agonists need to be produced to explore delta receptor pharmacology. The examination of nonanalgesic activities of delta ligands in opioid receptor knockout mice has been very informative while the convulsive effect of SNC 80 seems indeed delta receptor mediated, the addictive activity of Delt most probably results from mu receptor activation and the immunosuppressive action of NTI is mediated by a nonopioid mechanism. 

The role of Gpy, released from pertussis toxin-sensitive G proteins, in coupling activated receptor to effectors further complicates specificity. Delta opioids activate G protein-coupled inwardly rectifying K+ channels [50] activation of such channels occurs by direct binding of Gp-y to various regions of the channel [51]. Delta agonist-mediated increase in the release of Ca2+ from intracellular stores in NG108-15 cells is mediated by Gp-y subunits [52], and Gp antibodies inhibited DPDPE stimulated PLC-p activation and, therefore, Ins(l,4,5)P3-dependent Ca2+ release and smooth muscle contraction in intestinal smooth muscle cells of the guinea pig [46]. However, the Ga... 

In HEK cells coexpressing the delta opioid receptor and a constitutively active mutant of Gas and adenylyl cyclase type II, delta agonists cause Gfky-mediated stimulation of adenylyl cyclase type II [55]. Agonist action at delta receptors expressed in COS-7 cells or HEK 293 cells has been shown to stimulate the MAP kinase pathway, possibly mediated by Gfky subunits [56,57],... 

There are several indications that crosstalk between delta and other opioid systems may alter the pharmacology of delta agonists. For example, delta... 

Importantly, there are additional controls on the ability of delta agonist occupied receptor to activate specific G protein and downstream effectors that are thus far poorly understood. These include agonist-specific activated states of the receptor, the capacity of the delta receptor to form homocomplexes or heterocomplexes with other GPCRs, and accessory proteins that may scaffold and/or act in a functional capacity. 

The N-terminal tetrapeptides of D-Met-deltorphin and D-Ala-deltor-phins did not show preference for delta receptors over mu receptors. The common determinants concurring to the remarkably efficient targeting of deltorphins towards the delta receptors were identified through structure-activity relationship studies conducted on an extensive series of synthetic analogues. The following structural requirements explain why the deltorphins are such potent and selective delta agonists a phenolic side chain (Tyr) and a... 

Opioid Peptide-Derived Delta Antagonists, Inverse Delta Agonists, and Mixed Mu Agonist/Delta Antagonists... 

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