Abstract
Extensive evidence demonstrates functional interactions between the adrenergic and opioid systems in a diversity of tissues and organs. While some effects are due to receptor and second messenger cross-talk, recent research has revealed an extracellular, allosteric opioid binding site on adrenergic receptors that enhances adrenergic activity and its duration. The present research addresses whether opioid receptors may have an equivalent extracellular, allosteric adrenergic binding site that has similar enhancing effects on opioid binding. Comparison of adrenergic and opioid receptor sequences revealed that these receptors share very significant regions of similarity, particularly in some of the extracellular and transmembrane regions associated with adrenergic binding in the adrenergic receptors. Five of these shared regions from the mu opioid receptor (muOPR) were synthesized as peptides and tested for binding to adrenergic, opioid and control compounds using ultraviolet spectroscopy. Adrenergic compounds bound to several of these muOPR peptides with low micromolar affinity while acetylcholine, histamine and various adrenergic antagonists did not. Similar studies were then conducted with purified, intact muOPR with similar results. Combinations of epinephrine with methionine enkephalin or morphine increased the binding of both by about half a log unit. These results suggest that muOPR may be allosterically enhanced by adrenergic agonists.
Highlights
Opioid receptors mediate nociception and analgesia in a manner that is integrally linked with catecholamine function
Epinephrine bound to four of the five mu opioid receptor (muOPR) peptides (Figure 4), displaying biphasic high-affinity (Kd = 1 to 2 μM) and low affinity (Kd = 30 to 40 μM) components that were present in a number of other adrenergic antagonists such as norepinephrine (Table 2) and amphetamine (Figure 5), but not dopamine (Figure 6), which only displayed the low affinity binding
Our experiments demonstrate that muOPR and ADR manifest similar sequences, especially in their transmembrane regions and extracellular loops
Summary
Opioid receptors mediate nociception and analgesia in a manner that is integrally linked with catecholamine function. Co-functionality is such that ADR control the locomotor and reward effects of opioids [21] and knocking out α1b-adrenergic receptors and 5-HT2A receptors simultaneously eliminated the response of mice to amphetamine and cocaine, and to morphine [22]. Clinical and experimental studies suggest that a parallel enhancement of opioid receptors (OPR) by adrenergic agonists (but, notably, not antagonists) exists. The enhancement of opioid function by adrenergic agonists, amphetamines, has been observed in other systems as well, such as opioid-mediated reward and related behaviors [59,60,61,62,63,64,65]; glucose uptake in the brain [66]; and on guinea pig ileum contractions induced by morphine, which are enhanced by serotonin [67,68,69]. This paper reports an initial investigation of this possibility and explores the mechanistic implications of an allosteric mechanism for understanding opioid-adrenergic synergy
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