The pathway of opioid drugs into cellular structures

Opioid drugs penetrate cells, resulting in both high efficacy and side effects.

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Opioids, including natural and therapeutic opioids, activate opioid receptors in the body to alleviate pain and induce a feeling of well-being. However, the excessive use of opioids can lead to dependence and addiction and cause numerous deaths worldwide.

Researchers from the University of Geneva have studied the action of natural and therapeutic opioids on opioid receptors and found that therapeutic opioids can penetrate inside cells to activate intracellular receptors, whereas natural opioids only activate receptors on the cell surface. This could explain why opioid drugs trigger different physiological responses and severe side effects. The findings could lead to safer and more effective medications that better mimic natural opioids.

Opioid drugs are a class of drugs that act on the nervous system to produce pain relief, pleasure, and a sense of euphoria. They bind to specific receptors in the brain and other body parts, including cells. Researchers from the University of Geneva have developed new molecular tools to study opioid receptors’ functioning at unprecedented spatial resolution. 

They found that the location of GPCR activation modifies the response triggered by opioids, and membrane lipids types surrounding the GPCR influence the responses they transmit. The localization of receptors could explain the differences in effects and side effects triggered by natural and therapeutic opioids. The researchers plan to conduct in vivo experiments to confirm this hypothesis and design better-targeted therapeutics with improved efficacy and reduced side effects.

The fact that the localization of receptors changes the cellular responses could explain differences in effects and side effects triggered by natural and therapeutic opioids. 

Miriam Stoeber said, “To confirm that hypothesis, we are planning in vivo experiments, with the ultimate aim to design better-targeted therapeutics with improved efficacy and reduce side effects.” 

This experiment investigated how the subcellular location of G protein-coupled receptors (GPCRs) influences the signals they transmit in response to opioids. The researchers developed new molecular tools to study the functioning of opioid receptors at a high spatial resolution, allowing them to observe changes at different locations inside cells. 

They hypothesized that the location of GPCR activation could modify the response triggered by opioids and, consequently, the signals involved in pain relief. 

By studying the role of membrane lipids surrounding GPCRs, the researchers hoped to explain variations in the effects of opioid drugs and design better-targeted therapeutics with improved efficacy and fewer side effects.

To understand how opioids enter our cells, it’s important to know that cells have various mechanisms to allow substances to enter or exit them. Opioids can enter cells through endocytosis, which is the cellular process of taking in substances from outside the cell by engulfing them with a portion of the cell membrane. Once inside the cell, the opioids bind to specific opioid receptors located on the cell membrane’s surface or within the cell.

The binding of opioids to their receptors triggers a cascade of biochemical events inside the cell, which can lead to changes in the cell’s behavior and ultimately affect the organism’s behavior as a whole. For example, opioids can inhibit the release of certain neurotransmitters that transmit pain signals in the brain and spinal cord, thereby reducing pain perception. 

The researchers in this experiment developed new molecular tools to study the functioning of opioid receptors at a high spatial resolution. They used biosensors that allowed them to detect in living cells whether receptors present at specific locations in or on the cells are activated and can initiate a response. 

They also analyzed gene expression and protein regulation to understand the mechanisms responsible for the different responses triggered by G protein-coupled receptors (GPCRs) in response to opioids.

To investigate the role of membrane lipids, the researchers manipulated the types of lipids surrounding GPCRs using pharmacological and genetic tools. They then observed changes in the responses triggered by GPCRs in response to opioids.

The researchers conducted their experiments using living cells in vitro and in vivo. In vivo, experiments were planned to confirm the hypothesis that the localization of receptors changes cellular responses and to design better-targeted therapeutics with improved efficacy and fewer side effects.

The experiment results showed that the location of G protein-coupled receptors (GPCRs) activation modifies the response triggered by opioids. The researchers discovered that opioid drugs penetrate inside cells to activate intracellular receptors, whereas natural opioids are unable to enter cells and activate only receptors located on the cell surface. This difference in receptor location explains why opioid drugs trigger very different physiological responses from those induced by natural opioids. 

The researchers also found that the types of membrane lipids surrounding the GPCR influence the responses they transmit. These findings suggest that the localization of receptors is crucial in defining the response to opioid drugs and could help develop safer and more effective medications that better mimic natural opioids.

In summary, opioids can enter cells through endocytosis and bind to specific opioid receptors, leading to changes in the cell’s behavior and affecting the organism’s behavior as a whole. Understanding how opioids get into our cells is important for developing strategies to prevent and treat opioid addiction and overdose.

Journal Reference:

  1. Radoux-Mergault, Stoeber,etal. Subcellular location defines GPCR signal transduction. Science Advances. DOI: 10.1126/sciadv.adf6059