With around 187 people dying every day from an opioid overdose in the U.S., combatting the opioid overdose epidemic has become a mean challenge for the scientific community. According with the National Institute on Drug Abuse (NIDA) nearly 92, 000 Americans died from drug-involved overdose in 2020, of which approximately 75% involved opioids. Some examples of opioids include heroin, morphine, codeine, fentanyl, methadone, tramadol and other opioid analogs. Opioids are analgesic drugs consumed non-medically for euphoric feelings and medically for pain relief, although the last one comes with pharmacological side effects such as breathing difficulties and addiction which contribute to the current opioid crisis problem3.
The opioid system is one of the most important in regulating the response to nociception, i.e. the response of the nervous system to painful stimuli; the 1970s marked the beginning of its study with the first discoveries which suggested that there were "binding sites" in the central nervous system that were recognized by exogenous opioids such as morphine, leading later to the discovery of opioid receptors1. The opioid system is composed of a set of major endogenous opioid peptides (EOPs): β-endorphin, enkephalins and dynorphins, and four opioid receptors (ORs): μ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-opioid receptor (DOR) which are expressed throughout the central and peripheral nervous system and regulate important physiological functions such as analgesia, stress response, mood, reward, etc3.
Opioid receptors belong to class A of G protein-coupled receptors or GPCRs and signaled mainly through Gai/o, beta/gamma subunits and arrestins. At the synapse, they are localized in both pre- and postsynaptic compartments and their activation is generally related to inhibiting neurotransmission by hyperpolarizing the cell or reducing or potentiating neuronal activity4. Given their pathophysiological significance in pain, addiction and depression opioid receptors represent important pharmacological targets.
Morphine is one of the most widely used and proven analgesic for the treatment of severe acute or chronic pain conditions, but their use is overshadowed by their side effects and by the development of dependence and addiction. Morphine is an agonist of Mu opioid receptor (MOPR) and one of the objectives in the development of new opioids is to synthesize compounds with high analgesic power but without side effects like morphine does3. Therefore, the study of the different signal transductions triggered by the opioid-receptor interaction is of great importance. With this in mind one of the proposals is to take advantage of biased agonism, i.e. when the same receptor signals downstream through different signaling pathways triggered by different molecules2.
There are several reports that have addressed the differences in the mechanisms of transduction triggered by MOR, reporting that G-protein signaling is more associated with the analgesic effect, while the side effects are orchestrated via β-arrestin 2. However, opioids that prevent recruiting β-arrestin 2 do not address the problem since ligands that only minimally recruit β-arrestin 2 to MORs may also cause opioid side effects2. Therefore to understand better the functions of arrestins in MOR signaling, Shiraki et al., explored the function of β-arrestin 2 in MOR signaling using the SH-SY5Y cell line that endogenously expresses MOR and was modified through CRISPR/Cas9 to knock out β-arrestin 1 and 2 gene expression.
This report highlights a mechanism of β-arrestin pathway activation dependent on G protein activation, which contrasts with the idea that these signaling pathways are independent and compete with each other. The authors found that both β-arrestin 1 and 2 are involved in MOR internalization and downstream signaling activation of the β-arrestin pathway under Gi/o activation-MOR, being crucial the formation of β-arrestin/ β2-adaptin and clathrin heavy chain complex to mediates MAPK signaling5.
These findings highlight how G proteins and β-arrestins are involved in driving intracellular signaling and reinforce the role of β-arrestins in the physiological opioid system. If you are interested in learning more about the molecular details of this study, you can consult the article at the following link https://pubmed.ncbi.nlm.nih.gov/36502633/
1. Brownstein MJ. A brief history of opiates, opioid peptides, and opioid receptors. Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5391-3. doi: 10.1073/pnas.90.12.5391. PMID: 8390660; PMCID: PMC46725. https://pubmed.ncbi.nlm.nih.gov/35435616/
2. Faouzi A, Varga BR, Majumdar S. Biased Opioid Ligands. Molecules. 2020 Sep 16;25(18):4257. doi: 10.3390/molecules25184257. PMID: 32948048; PMCID: PMC7570672.
3. Manhapra A. Complex Persistent Opioid Dependence-an Opioid-induced Chronic Pain Syndrome. Curr Treat Options Oncol. 2022 Jul;23(7):921-935. doi: 10.1007/s11864-022-00985-x. Epub 2022 Apr 18. PMID: 35435616.
4. Reeves KC, Shah N, Muñoz B, Atwood BK. Opioid Receptor-Mediated Regulation of Neurotransmission in the Brain. Front Mol Neurosci. 2022 Jun 15;15:919773. doi: 10.3389/fnmol.2022.919773. PMID: 35782382; PMCID: PMC9242007.
5. Shiraki A, Shimizu S. The molecular associations in clathrin-coated pit regulate β-arrestin-mediated MAPK signaling downstream of μ-opioid receptor. Biochem Biophys Res Commun. 2023 Jan 15;640:64-72. doi: 10.1016/j.bbrc.2022.11.098. Epub 2022 Nov 30. PMID: 36502633.