Receptors for opioids

Kieffer BL. Recent advances in molecular recognition and signal transduction of active peptides receptors for opioid peptides. Cell Mol Neurobiol 1995 15 615— 635. 

Boyce R, Li G, Nestler HP, Suenaga T, Still W Clark, Peptidosteroidal receptors for opioid peptides. Sequence-selective binding using a synthetic receptor library, J. Am. Chem. Soc., 116 7955-7956, 1994. 

The finding that the immune and neuroendocrine systems both express receptors for opioids and for ACTH and that both systems can synthesize and release peptides active at these receptors, led to the suggestion that the immune system functions as a sensory organ (Blalock, 1984, 1999) and that this forms the basis for the interaction betw een the tw o systems. It is v ell knovm that the nervous system responds to a variety of stimuli and, w hen appropriate, releases neurotransmitters and hormones that enable an appropriate reaction to these stimuli or stresses. This can include changes in immune system function. Blalock proposed that the immune system also responds to particular stimuli, in this case environmental changes that would not be readily detec ted by the nervous system, such as the presence of bacteria or viruses. In response, the immune system releases a variety of compounds, including peptide hormones that will alter both immune and nervous system function. 

Credit for recognition of the potential existence of receptors for opioids on cells of the immune system is given to loseph Wybran in the laboratory of Govaerts. In 1979 he reported modulation of the function of human T cells, purified from normal peripheral blood, by exogenous and... 

Since P-endorphin is located within the hypothalamus and the pituitary, and has a relatively longer duration of action, it tends to be viewed as a neurohormone. Enkephalins, on the other hand, are more extensively distributed, are very rapidly degraded, and are primarily located in synaptosomal areas. The additional observation that enkephalin release following depolarization of brain (and intestinal) tissues is calcium dependent makes it more realistic to categorize them as neurotransmitters or modulators of synaptic function. Binding sites (receptors) for opioids are found, particularly in synaptosomal brain fractions. The enkephalins are located in neurons whose distribution correlates well with that of the receptors. In fact, regional distribution of peptides and their receptors are closely parallel, as would be predicted for a neurotransmitter system. 

Boyce, R., Li, G., Nestler, H. P., Suenaga, T. and Still, W. C. (1994) Peptidosteroidal receptors for opioid peptides. Sequence-selective binding using a synthetic receptor library, J. Am. Chem. Soc. 116, 7955 Cheng, Y. A., Suenaga, T. and Still, W. C. (1996) Sequence-selective peptide binding with a peptido-A,B-trans-steroidal receptor selected from an encoded combinatorial receptor library, J. Am. Chem. Soc. 118, 1813-1814. 

The pharmacological and/or adverse effects of a drug can be reversed by co-administration of drugs which compete for the same receptor. For example, an opioid receptor antagonist naloxone is used to reverse the effects of opiates. Drugs acting at the same site with opposite effects also can affect each other, e.g. the reduction in the anticoagulant effect of warfarin by vitamin K. 

A 17 amino acid long peptide sequentially related to opioid peptides in particular dynorphin A. OFQ/N is inactive at the 5, k, and p opioid receptors, but binds to its own NOP receptor (formerly ORL-1, for opioid receptor like-1). In contrast to opioid peptides, OFQ/N has no direct analgesic properties. OFQ/N is the first example for the discovery of a novel neurotransmitter from tissue extracts by using an orphan receptor as bait. Centrally administered in rodents, OFQ/N exerts anxiolytic properties. OFQ/N agonists and antagonists... 

The GABAB-receptors, the muscarinic M2- and IVU-receptors for acetylcholine, the dopamine D2-, D3-and D4-receptors, the a2-adrenoceptors for noradrenaline, the 5-HTiA F-receptors for serotonin, and the opioid p-, 8- and K-receptors couple to G proteins of the Gi/o family and thereby lower [1] the cytoplasmic level of the second messenger cyclic AMP and [2] the open probability ofN- andP/Q-type Ca2+ channels (Table 1). The muscarinic Mr, M3- and M5-receptors for acetylcholine and the ai-adrenoceptors for noradrenaline couple to G proteins of the Gq/11 family and thereby increase the cytoplasmic levels of the second messengers inositol trisphosphate and diacylglycerol (Table 1). The dopamine Dr and D5-receptors and the (3-adrenoceptors for noradrenaline, finally, couple to Gs and thereby increase the cytoplasmic level of cyclic AMP. 

Opioid regulation of chemokine and chemokine receptor expression has several disease- related implications. Viral infection by HIV-1 can be enhanced with opioids that activate MOR while the opposite can be true for opioids that activate KOR. Increased levels of HIV-1 coreceptors, such as CCR5 and CXCR4, can promote viral binding and trafficking of HIV-1 virally infected cells. It is likely that this allows the viral disease to progress in the immune cells of the blood in addition to neurological reservoirs. Alterations of chemokine receptor expression will not only affect viral infection, but also alter immune system function. In certain diseases... 

The opioid antagonists naloxone and naltrexone bind to aU three opioid receptors, p, K, and 8. These compounds are antagonists due to their inability to elicit downstream effects of these receptors once bound (Sarton et al. 2008 Yaksh and Rudy 1977). Interestingly, both antagonists have a high binding affinity for MORs. Naloxone is used to reverse the effects of an acute opioid overdose because of its rapid onset of action. Naltrexone elicits similar actions, but has a longer onset and duration of action and hence, is used for the maintenance of treatment for opioid addicts. 

Different peptides from the same gene product (met and leu enkephalin, substance P and neurokinin A). The former two act on the same receptor, the delta opioid receptor, whereas the latter act on different receptors, the neurokinin 1 and 2 receptors. Despite this, the receptors for the neurokinins produce the same direction of effect, a slow depolarisation, even though their distribution differs. 

There is little new with regard to the mu receptor, the main target for opioid drugs. The receptor is remarkably similar in structure and function in all species studied so animal studies will be good predictors for clinical applications. Although there have been suggestions of subtypes of the receptor, the cloned mu receptors have all been identical. 

Not many nonpeptide agonists are yet available, but such compounds have been described — for example, in the angiotensin, CCK, and opioid receptor systems. In fact, for a few receptors, such as the somatostatin, ghrelin, and complement C5A receptors, basically all compounds found by screening using binding assays are agonists. In contrast, for the majority of receptors for which... 

Herz A. Implications of the multiplicity of opioid receptors for the problem of addiction. Drug Alcohol Depend. 25 125, 1990. 

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