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Researchers hope peptides can be a key to developing safer opioids. VICTOR TORRES/Stocksy
  • New research undertaken by American and Chinese researchers may pave the way for safer opioid painkillers, thanks to the use of cryo-electron microscopy (cryo-EM) to examine the detailed structures of opioid receptors.
  • By analyzing the connections between these receptors and their natural peptide partners, the researchers hope to inspire the development of peptide-based or peptide-inspired medications with fewer severe side effects.
  • This research could revolutionize pain management by mitigating risks such as addiction, numbness, and potentially fatal breathing problems associated with current opioid medications.

Opioids alleviate pain by imitating a natural pain-relief process in our nervous system.

They are the most effective and powerful painkillers available.

However, they also have side effects, some of which can be severe. These include numbness, addiction, and breathing problems, which can result in fatal overdoses.

For many years, researchers have been attempting to address the issue of side effects in different ways, all of which involve one or more of the four opioid receptor subtypes. So far, those efforts have not been successful.

One ongoing approach is the development of peptide-based or peptide-inspired small molecule medications.

Peptides are brief sequences of amino acids, similar to shorter versions of proteins.

Specific naturally occurring peptides, known as endogenous peptides, attach to opioid receptors on cell surfaces to produce a pain-relieving effect, also called an analgesic effect.

Analgesics are different from anesthetics because they don’t “shut down” nerves to numb the body or change one’s state of consciousness.

The goal is to develop a peptide-based drug that provides significant pain relief without causing numbness, altering consciousness, or leading to digestive, respiratory, or addiction problems.

A new study, published in the journal Cell, helped researchers understand how these receptors choose specific peptides and how they send signals to drugs.

The researchers say the information could one day aid drug developers in creating safer medications for severe pain relief.

Using a technique called cryogenic electron microscopy (cryo-EM) and a series of experiments on cells, the researchers looked at the detailed structures of natural peptides when they’re connected to all four opioid receptors.

They said they discovered how specific natural opioid peptides recognize and activate these receptors. In some experiments, they also used drug-like compounds to see how they activated the receptors.

When the receptors are sending signals in cells, the cryo-EM images showed what they look like in their “active state” when connected to their helper proteins, called G protein effectors. This offered a detailed look at how peptides and receptors interact.

By understanding these interactions, scientists may be able to design drugs that target specific opioid receptor types and create specific signaling outcomes that might be more helpful than traditional opioids.

This could lead to better pain relief without as many side effects.

Jeffrey F. DiBerto, PhD, the co-first author on the study, played a key role in conducting pharmacological experiments to comprehend the signaling mechanisms of these receptors.

Speaking to Medical News Today, DiBerto explained the background to this research, saying, “the human body expresses four opioid receptor subtypes that are activated by endogenous opioid peptides. These peptides bind to these subtypes with varying levels of selectivity, consequently activating them to modulate responses to pain stimuli.”

Using a technique called cryogenic electron microscopy, we solved the high-resolution structures of the four opioid receptor subtypes bound to their respective, highly-selective peptides and in complex with a signaling molecule called a heterotrimeric G protein.

Jeffrey F. DiBerto

“By using models of these structures, we could infer the interactions between opioid peptides and receptors, which in turn guided biochemical studies we used to understand how these interactions lead to receptor activation,” DiBerto explained.

By changing or mutagenizing receptors’ amino acids to disrupt these interactions, we observed changes in signalling. In this study, we measured the signalling through the aforementioned G proteins and another signalling protein called beta-arrestin. There is some evidence that scientists can use this differential signalling through these G protein and arrestin molecules for therapeutic gain – preserving opioid painkilling while decreasing side-effects, such as nausea or respiratory depression.

Jeffrey F. DiBerto

“Altogether, this study provides structural and biochemical insights into how these endogenous opioid peptides recognize and activate their receptors, providing basic science insights into the molecular pharmacology of the endogenous opioid system, as well templates for rational drug design at these receptors, DiBerto noted.

Dr. Medhat Mikhael, a pain management specialist and medical director at the Spine Health Center at Memorial Care Orange Coast Medical Center in California who was not involved in this research, told MNT that “this is much needed research that looks to create an opioid peptide that would mimic our endogenous opioids and selectively bind the four opioid receptors subtypes in a similar fashion that our own endogenous opioids do, without creating the undesired and serious side effects like addiction and respiratory depression.”

I believe reaching for such a drug is close and it will make a significant impact in the way we treat pain. This would represent an exciting new chapter in medicine.

Dr. Medhat Mikhael

While DiBerto notes that this research provides insight into the molecular pharmacology of the endogenous opioid system, current opioid drugs are small molecules and modifying them may not be straightforward.

However, “this study provides a molecular framework for designing drugs, including those belonging to novel scaffolds, that act selectively or with mixed actions as opioid receptor subtypes,” DiBerto said.

Mikhael agreed, noting the potential benefits of creating new opioid peptides, saying they “will allow acute and chronic pain to be treated in a much safer way with much less risk of developing life-threatening side effects like addiction, respiratory depression and others.”

Creating such a peptide will bind the opioid receptors subtypes in the same fashion our own endogenous opioids does has the potential results of alleviating the pain without creating the undesired and dangerous side effects that so many fear and/or experience when taking this powerful pain medicine.

Dr. Medhat Mikhael

DiBerto highlighted the importance of research into this topic, saying “drugs exhibiting unique pharmacological properties at their receptors may prove to be safer than currently available opioid medications, which are currently responsible for thousands of deaths in the United States each year.”