Opioid receptor subtypes delta

Sofuoglu M, Portoghese P, Takemori A. Differential antagonism of delta opioid agonists by naltrindole and its benzofuran analog (NTB) in mice evidence for delta opioid receptor subtypes. 

Perez, L. and Lysle, D.T., Conditioned immunomodulation Investigations of the role of endogenous activity at mu, kappa, and delta opioid receptor subtypes, J. Neuroimmunol.,19, 101,1997. 

Rothman and Westfall [3,4], divided the delta receptor population into two components one coupled to mu opioid receptors, and the other acting alone. The third hypothesis combined these ideas, by suggesting that the delta receptors that interact with the mu opioid receptors are different molecular entities from those that act alone [5,6]. A definitive test of the above hypotheses would be to identify two or more delta receptor proteins by molecular cloning. The cloning of the human delta opioid receptor [7] was the fortunate outcome of a larger project in our laboratory to clone of the cDNAs encoding putative delta opioid receptor subtypes. 

Since at the time of the described studies it was thought that the two delta receptor antagonists naltriben (NTB) and 7-benzylidenenaltrexone (BNTX) were selective for the proposed delta-2 and delta-1 receptor subtypes, respectively [19], the relatively high affinity of NTB for the expressed receptors (as compared to BNTX, see Table 1) was thought to be consistent with the cloned human delta receptor being of the delta-2 opioid receptor subtype. 

Distinct genes for delta opioid receptor subtypes however, have not been identified, reducing the probability that delta opioid receptor subtypes exist as distinct molecular entities. On the other hand, this does not eliminate the possibility that pharmacological delta opioid receptor subtypes can be produced by alternative splicing from the cloned delta receptor genomic sequence, as was found for the other opioid receptors [28]. However, there is no evidence for alternative splicing for the delta opioid receptor of this at... 

The Delta Opioid Receptor Subtypes and Pain Modulation... 

The work of Devi and associates [22] provided a potential molecular mechanism for mu-delta interactions and a physical basis to explain biochemical observations of a mu-delta opioid receptor complex [23,24]. Their work and the efforts of others [25] have clearly demonstrated that mu and delta receptors can form heterodimers, leading to synergistic interactions and the generation of novel signaling units. This work, in other words, provides a molecular mechanism to explain how it is possible for three basic types of opioid receptors to form a greater number of pharmacologically defined opioid receptor subtypes. 

In vitro and in vivo studies conducted in the 1980s and 1990s clearly demonstrated synergistic interactions in vivo between mu and delta receptors that were most simply explained by a mu-delta opioid receptor complex. The failure to clone opioid receptors corresponding to the postulated mu-delta opioid receptor complex, as well as other opioid receptor subtypes defined... 

EVIDENCE FOR A DELTA OPIOID RECEPTOR SUBTYPE BEING RESPONSIBLE FOR OPIOID-INDUCED CARDIOPROTECTION... 

Delta Receptors. There has been considerable interest in 6 opioid agonists because they exhibit antinociceptive effects without the side effects associated with p, opioid receptor agonists. Antinociceptive activity was first demonstrated with 6-selective opioid peptides (see Ref 218 for a review), and more recently with nonpeptidic 6-selective agonists (see Refs. 219-222 for reviews). Of particular interest is the activity of 6 agonists in inflammatory and neuropathic pain (220). Delta opioid receptors also modulate fx opioid receptors and, as discussed earlier, one classification of 6 opioid receptor subtypes was based on their association with p, opioid receptors. There is now considerable evidence that interaction between the two receptor types can alter the activity of p. opioid agonists. Delta agonists... 

Mika J, Przewlocki R, Przewlocka B (2001) The role of delta opioid receptor subtypes in neuropathic pain. Eur J Pharmacol 415 31-37... 

Four principal opioid receptor subtypes, designated as mu, kappa, delta, and sigma, have been characterized [1,2]. A newer receptor classification system utilizes labels OPRj, OPR and OPR, which correspond to mu, kappa, and delta receptors respectively [1,3,8]. Mu receptors (OPR ) mediate supraspinal analgesia, as well as respiratory depression, nausea and vomiting, miosis and bowel hypomotil-ity. Mu receptors also mediate euphoria and physical and psychological dependence, and are responsible for the increased release of prolactin and growth hormone [1,2]. 

Progress in the molecular characterization of opioid receptors has been slower than for other cell-surface receptors and, to date, none has been sequenced or cloned and the second messengers mediating opioid actions are still unknown. The literature in this area has been reviewed in 1990 by Lo and Smith [11], who cite three main problems with the opioid receptor it is difficult to solubilize, there are no simple biochemical assays to test the functional integrity of an isolated receptor extract and there are at least three receptor subtypes (designated as mu, kappa and delta). 

Fig. 9.8 Examples of rule-of-three compliant molecules that have biological activity better than 10 nM. Under each molecule, the following information is included molecule name, MW, ClogP, the biological activity type, value and target. Target names are as follows D3 and D4 - dopaminergic receptor types 2 and 3 AChE and BChE - acetyl- and butyryl-choline esterases PRa and PRb - progesterone receptor types A and B H] and H3, histamine receptor types 1 and 3 5-HT2a, 5-HT2b, 5-HT2c, 5-HT3, 5-HT4 - serotonin receptor subtypes 2A, 2B, 2C, and types 3 and 4 DAT, NET, 5-HTT - dopamine, norepinephrine and serotonin transporter proteins /X], /x.2, S, ki, ks - opioid receptor types mu-1, mu-2, delta, kappa-1 and kappa-3 5a-Rl and 5o -R2 - 5-alpha-reductase isozymes 1 and 2 Flt-1-fms-like tyrosine kinase receptor.

Fowler, C.J. and Fraser, G.L. Mu-, delta-, kappa-opioid receptors and their subtypes. A critical review with emphasis on radioligand binding experiments, Neurochem. Int. 1994, 24, 401-426. 

Jiang, Q., Takemori, A.E., Sultana, M., etal. Differential antagonism of opioid delta antinociception by [D-Ala2,Leu5,Cys6]enkephalin and naltrindole 5 -isothiocyanate evidence for delta receptor subtypes, J. Pharmacol. Exp.Ther. 1991, 257, 1069-1095. 

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