Will Biased Ligands Be the Opioids of the Future?

Jane C. Ballantyne; Charles Chavkin


Pain. 2020;161(9):1945-1948. 

In This Article

Abstract and Introduction


The principal opioid medications used in clinical practice act by binding to the endogenous μ-opioid receptors to initiate specific cellular signaling events that result in the observed pharmacological responses. These responses are initiated by G-protein activation, which affects calcium and potassium ion channel conductance to inhibit neuronal excitability and reduce neurotransmitter release. Sustained opioid receptor activation results in recruitment of β-arrestin, which is a scaffolding protein that desensitizes G-protein signaling but also activates various kinase cascades that can potentially result in other opioid receptor-mediated effects. Thus, opioid receptor activation results in 2 forms of cellular signaling: an arrestin-dependent and an arrestin-independent set of responses. Recently, tremendous excitement in the analgesic drug development field has been generated by the realization that different opioid drugs might preferentially activate one pathway or another. This concept is called pharmacological "bias" or "functional receptor selectivity," and it has been proposed that certain opioids that preferentially activate the arrestin-independent pathway might be safer analgesics.

The idea that opioid-induced analgesia could be associated specifically with G-protein-dependent signaling, whereas certain adverse effects could be medicated by β-arrestin arose from the finding that β-arrestin 2 knockout mice showed enhanced morphine analgesia with less respiratory depression, tolerance, and constipation.[3,5,22] So began decades of investment and research seeking a "biased" opioid agonist that might provide better, more sustainable, analgesia without respiratory depression or other potentially catastrophic side effects. Although respiratory depression is potentially the most catastrophic of adverse opioid outcomes, other side effects including opioid tolerance, hyperalgesia, constipation, and addiction liability seriously limit the utility of opioid drugs in the treatment of chronic pain. The premise of the recent investigations into biased opioids is that G-protein signaling is responsible for the desirable effects (analgesia), whereas the arrestin-dependent effects (respiratory depression, constipation, and euphorigenic effects) are mediated by arrestin-dependent signaling. That dichotomy has recently been challenged.[11,12] However, G-biased opioid agonists have been identified,[10,15] and their potential therapeutic advantages are worth exploring. We do know that the neural circuits controlling these different pharmacological responses are anatomically distinct (eg, the respiratory centers in the brainstem are distinct from the reward centers in the midbrain), but whether mu-opioid receptor signaling in these different circuits use distinct signaling cascades is not yet known. Nevertheless, efforts to develop safer analgesics are certainly justified by the unmet clinical need for effective treatments for chronic pain. Here, we will focus on the potential role for biased opioid ligands in reducing 3 important adverse opioid effects: respiratory depression, abuse potential, and analgesic tolerance.