Delta receptors interactions

Tramadol is a dual-mechanism, central-acting analgesic. It interacts weakly with p opioid receptors and to a lesser extent at kappa and delta receptors. Interactions at these receptors provide weak opioid agonist properties. It also has effects on noradrenergic and serotonergic reuptake proteins and accentuates spinal and supraspinal monamine-based analgesia [5,6,7]. Tramadol s opioid and non-opioid sites of action appear to act additively to provide more effective pain relief. Of the two tramadol enantiomers, the (+) enantiomer acts as a p receptor agonist and as a 5-HT reuptake inhibitor, while the (-) enantiomer is a norepinephrine reuptake inhibitor [2,5]. 

The third prohormone from which opioid peptides are derived is pro-opiomelanocortin, which yields a number of nonopioid and opioid peptide products (O Donohue and Dorsa 1982). Of these products, beta-endorphin, an untriakontapeptide isolated from camel pituitary gland by Li and Chung (1976)) is thought to interact primarily with mu and delta receptors. 

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. 

It is pertinent to ask whether interaction of the delta receptor with particular G protein subunit combinations leads to specificity for particular signaling pathways. For example, in rat dorsal root ganglia delta opioid receptors inhibit adenylyl cyclase [27] but do not couple to Ca2+ channels [28]. A variety of experimental approaches have shown that the delta receptor generally appears to be promiscuous with regard to its interaction with members of the Gai/o family. However, those experiments do confirm that this receptor does not normally couple to other Ga families, although this can be seen in transfected systems (Table 1). 

In many systems delta receptors appear to be promiscuous with regard to their ability to interact with a variety of G proteins of the Gi/o family. The actual combinations of Ga and Gpy with which the receptor interacts are likely to be governed by the types and amounts of G protein expressed in particular cells, and the physiological and pharmacological outcome by the ability of particular G proteins to modulate various downstream effectors. 

Conformational analyses of JOM-13 and [L-Ala3]DPDPE have proven to be critical for the determination of the bioactive conformation of enkephalin-like peptides at the delta receptor. H-NMR studies of JOM-13 in aqueous solution revealed that this tetrapeptide exists in two distinct conformations on the NMR time scale as evidenced by two sets of resonances [63]. Large differences in the observed chemical shifts and coupling constants for the D-Cys2 residue in the two conformers suggested that the major differences between the two NMR conformers reside in the disulfide portion of the molecule however, a paucity of conformationally informative nuclear Overhauser enhancement (NOE) interactions precluded the development of a detailed structural model from the NMR studies. In order to develop such a model a thorough conformational analysis of JOM-13 was undertaken, in which the NMR data were complemented by x-ray diffraction results and by molecular mechanics calculations [64]. The results indicate that the 11-... 

Enkephalins could be implicated in dopamine mesoaccumbens-depen-dent appetitive motivation and behavioral positive reinforcement by separated mechanisms involving both mu and delta receptors. Activation of the former in heroin abusers produces sedation and overstimulation, lack of vigilance, and possibly fear. These effects cannot be reached with dual inhibitors, and one can speculate that this is related to an increased level of endogenous enkephalins leading to a preferential interaction with delta receptors for both binding and anatomical reasons. 

The main purpose of this chapter is to review the evidence for delta-mu interactions in the context of recent research advances that reveal molecular mechanisms by which combinations of receptors might create new receptors with different pharmacological profiles. 

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... 

Tortella FC, Robles L, Holaday JW. The anticonvulsant effects of DADL are primarily mediated by activation of delta opioid receptors interaction between delta and mu-receptor antagonists. Life Sci 1985 37 497-503. 

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