Opioids activate GPCRs to produce powerful analgesic actions but at the same time induce side effects and generate tolerance, which restrict their clinical use. Reducing this undesired response profile has remained a major goal of opioid research and the notion of 'biased agonism' is raising increasing interest as a means of separating therapeutic responses from unwanted side effects. However, to fully exploit this opportunity, it is necessary to confidently identify biased signals and evaluate which type of bias may support analgesia and which may lead to undesired effects. The development of new computational tools has made it possible to quantify ligand-dependent signalling and discriminate this component from confounders that may also yield biased responses. Here, we analyse different approaches to identify and quantify ligand-dependent bias and review different types of confounders. Focus is on δ opioid receptor ligands, which are currently viewed as promising agents for chronic pain management. LINKED ARTICLESThis IntroductionOpioids are the most effective analgesics known but their clinical use is limited by a compromise between maintaining analgesic efficacy on the one hand and controlling side effects and development of tolerance on the other (Dworkin, 2009). Not surprisingly then, improving the side effects profile and reducing the potential for analgesic tolerance have remained major goals in opioid receptor research. Within this context the notion of 'biased agonism' has raised considerable interest as a means of separating desired actions from undesired effects of opioid analgesics. This new pharmacological concept refers to the ability of certain receptor ligands to stabilize the receptor into conformations that distinctively engage specific signalling partners, thus directing pharmacological stimuli towards desired responses. As such, biased ligands may constitute a powerful means of separating analgesic actions from undesired effects of opioid analgesics. However, to fully exploit this opportunity, we must be able to confidently identify ligands of interest and evaluate which of their responses contribute to analgesic efficacy and which support undesired actions. The development of new quantification tools (Rajagopal et al., 2011;Kenakin et al., 2012;Rajagopal, 2013) has not only made this identification possible, but should allow us to verify novel hypotheses with respect to the type of signals responsible for desired and undesired effects of opioids. Here, we review how to identify and quantify ligand-dependent bias and also examine the extent to which an imbalance in signalling versus internalization responses may be a desirable property as a predictor of ligand potential for generating tolerance. Focus will be on δ opioid receptor ligands (for nomenclature see Alexander et al., 2013), which are currently viewed as promising agents for chronic pain management (Gaveriaux-Ruff and Kieffer, 2011a;Gaveriaux-Ruff et al., 2011b) Biased responses versus biased agonism 'Biased agonism' is a term tha...
Traditional assays that monitor cAMP inhibition by opioid receptor ligands require second-messenger accumulation over periods of 10-20 minutes. Since receptor regulation occurs within a similar time frame, such assays do not discriminate the actual signal from its modulation. Here we used bioluminescence resonance energy transfer to monitor inhibition of cAMP production by d-opioid receptor (DOR) agonists in real time. cAMP inhibition elicited by different agonists over a period of 15 minutes was biphasic, with response buildup during the first 6 to 7 minutes, followed by a second phase of response decay or of no further increment. The rate at which the cAMP response disappeared was correlated with operational parameters describing ligand efficiency [log(t/K A )] to promote Ga i activation, as well as with ligand ability to promote internalization during the time course of the assay. Thus, ligands that displayed low signaling efficiency and poor sequestration (SB235863 ([8R-(4bS*,8aa,8ab,12bb)]7,10-dimethyl-1-methoxy- , which displayed high signaling efficiency and internalization. Moreover, inhibition of internalization by dynasore reduced or abolished response decay by internalizing ligands. Unlike acute responses, endocytic profiles were not predictive of whether an agonist would induce prolonged cAMP inhibition over sustained (30-120 minutes) DOR stimulation. Taken together, the data indicate that ligand ability to evoke Gprotein activation or promote endocytosis was predictive of response duration over short, but not over sustained periods of cAMP inhibition.
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