Opioid receptor complex

Application of the SCM method to the opioid receptor subtypes (187,188) supported the experimental evidence of subtype specificity in the process of heterodimerization of these receptors (96). Although likely heterodimerization interfaces of the 5-p and 5-k opioid receptor complexes were predicted using the SCM method, the application of this procedure to explore the putative interface between p and k opioid receptors resulted in a null set for residues that indicates the absence of a predicted dimerization interface. This result is in full agreement with previous experimental observations (96). 

Chakrabarti S, Law PY, Loh HH. Distinct differences between morphine- and i)-Ala2..Y-McPhe4,Gly-ol5]-enkephalin-mu-opioid receptor complexes demonstrated by cyclic AMP-dependent protein kinase phosphorylation. J Neurochem 1998 71 231-239. 

At the time these studies were conducted, two types of delta receptors were postulated a delta receptor associated with a mu receptor, that together comprised the mu-delta opioid receptor complex, and a delta receptor... 

Studies with the irreversible mu antagonist beta-FNA provided a linkage between the in vitro ligand binding evidence for a mu-delta opioid receptor complex and the in vivo evidence described above [18]. As noted above, in vivo administration of beta-FNA blocks delta agonist modulation in the antinociception models and delta antagonist effects in the seizure, endotoxic shock, and striatal cAMP models. As reported by Rothman et al. [18], either pretreating membranes with beta-FNA or ICV administration of... 

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... 

Rothman RB, Holaday JW, Porreca F. Allosteric coupling among opioid receptors evidence for an opioid receptor complex. In Herz A, ed. Handbook of Experimental Pharmacology. Opioids. Vol. 104. Berlin Springer-Verlag, 1992 217-237. 

Rothman RB, Mahboubi A, Bykov V, Kim C-H, Jacobson AE, Rice KC. Probing the opioid receptor complex with (+ )-trans-SUPERFIT I Evidence that [D-Pen2,D-Pen5]enkephalin interacts with high affinity at the cx binding site. Peptides 1991 12 359-364. 

Schoffelmeer AN, Yao Y-H, Simon EJ. Cross-linking of human 1251-beta-endorphin to a mu-delta opioid receptor complex in rat striatum. Eur J Pharmacol 1989 166 357-358. 

The classical opioid receptors, mu, delta, and kappa, have led to an even further definition of the relative pharmacology previously associated with them [12]. Moreover, it has more recently been reported that opioid receptors can exist as heterodimers [13]. This remarkable discovery opens the future of ligand design to target these dimeric and potentially oligomeric forms of the opioid receptor complexes. 

The authors favour a mode of opioid action in which an N-dealkylase enzyme is first activated either by an endogenous substrate (such as an enkephalin or endorphin which lack N-alkyl substituents) or an exogenous opioid-receptor complex (the enzyme incidentally N-de-alkylates the opioid). The activated enzyme then acts upon an unknown physiological substrate to yield a product which ultimately produces biological responses typical of opioids. Opioid antagonist-receptor complexes fail to activate the enzyme in this scheme. 

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