Skip to comments.Activation of opioid receptor uncovered
Posted on 11/27/2019 12:53:47 PM PST by Red Badger
Together with colleagues from Shanghai, Brussels, Canada and the USA, researchers from the University of Bonn have uncovered the binding mechanism of an important pain receptor. The results facilitate the development of new active substances. The opioids used today to treat severe pain can be addictive and sometimes have life-threatening side effects. The results of this new research are published in the renowned journal Science Advances.
Opioids are among the most effective painkillers available today. They include, for instance, morphine or oxycodone, which has been prescribed very carelessly in the USA, with serious consequences: Hundreds of thousands of patients have become addicted; many of them later ended up on drugs such as heroin or fentanyl.
Oxycodone binds to so-called opioid receptors in the body. There are three different types: MOP, DOP and KOP. The painkillers available to date mainly activate the MOP (also called μ-opioid receptor). However, stimulating MOP can not only be addictive, it can also have life-threatening side effects. The most serious is respiratory paralysis, which is why the most common cause of death after heroin use is respiratory arrest.
"Drugs that selectively bind to the DOP receptor probably do not have these dramatic side effects," hopes Prof. Dr. Christa Müller from the Pharmaceutical Institute at the University of Bonn. The emphasis is on "selective": The opioid receptors are so similar that many drugs activate all three forms. In order to find substances that only dock to the DOP receptor, it is therefore necessary to know exactly what happens during the binding process.
Spatial structure made visible down to the atomic level
The current study can now answer this question. "We have activated the DOP receptor with two different molecules, purified the complex and then elucidated its structure using X-rays," explains Tobias Claff, who carried out the majority of the experiments. For this purpose, the complex of receptor and active substance is transformed into a crystalline state. The crystal lattice deflects the X-ray light in a characteristic manner. The intensity distribution of the diffracted radiation can therefore be used to deduce the spatial structure of the complex, right down to the arrangement of each individual atom.
"This enabled us to show which parts of the receptor are responsible for binding the drugs," says Claff. "This knowledge should now enable the development of targeted new substances that only activate DOP." There is great interest in such drugs, not least because, unlike its MOP counterpart, the DOP receptor is not primarily effective against acute pain, but against chronic pain. This is currently very difficult to treat.
X-ray crystallography is not a new technique. However, the structure of G protein-coupled-receptors (including opioid receptors) could not be resolved until recently. These membrane proteins are located in the thin, fat-like membrane that surrounds the cell contents like a kind of bag. Their fat solubility means that they have to be stabilized at great effort during crystallization. Otherwise they denature and change their spatial structure as a result. "There are only a few laboratories in the world that are capable of dealing with these problems," emphasizes Christa Müller.
At the University of Bonn, aspiring pharmacists can go abroad during their master's or state examination program. The Institute has a broad network of cooperation partnersa fact that is regularly rated very positively in the CHE University Ranking. Tobias Claff used this opportunity: "I spent a year of my master's program at the iHuman institute of the ShanghaiTech University," he explains. "In the last few years, the crystallography of membrane proteins has been crucially advanced there." Claff learned the complex method in Shanghaia know-how that now also benefits his home university, to which he has meanwhile returned.
Prof. Müller emphasizes that it is not often that a master's student tackles such a complex problem. "This success is an extraordinary achievement," she says. "It also demonstrates the excellent position of the Pharmacy School with its international exchange program."
I wonder if drugs that selectively target the other opioid receptors would be effective for pain in people like me, for whom opioids give no relief. They sure cause plenty of side effects, though.
Eventually we will have designer drugs that target specific pain pathways, not just a blanket coverage like opioids. It’ll be like a laser guided bomb instead of a carpet bomb.............
Wow. Success could be worth a Nobel Prize.
Up with DOP, down with MOP!
Many have found pain relief from kratom. For me, it mimics the euphoria and energy provided by opiates, but since I don’t have pain, I don’t know about those effects. I believe it hits a kappa or mu receptor, I forget which, and causes no respiratory depression. Of course, it is addictive as well. It’s illegal in some states. Immodium hits another opiate receptor. I’ve read it can ameliorate withdrawal symptoms of opiates, but I don’t think it has any pain relieving qualities. Although 90% of online info on kratom is worthless, you might find some gems. But if opiates or opioids don’t help, conceivably kratom may not, either.
I won’t take any herb or “natural remedy” that has not been thoroughly tested.
For pain, I usually take ibuprofen. I have gone to physical therapy many times for pain; it works quite well, without any side effects. I’m currently going for complications from surgery.
using opioids to control pain may lead to physical addiction, but once the pain is relieved, you can wean the patient off the opioids.
and some people with chronic pain can be controlled and live a normal life with a stable dose of narcotics.
This is not addiction, which refers to drug seeking behavior and a gradual increase in the use of all sorts of drugs to get high
One is giving a drug so a person can lead a normal life, the second is using all sorts of drugs to get high and escape from life's burdens.
the cure fort this is (guess what) religion, to give meaning to life. Christians insist we can offer our sufferings to God as a prayer, and that bearing suffering with patience leads to us being more sympathetic to others who suffer; Buddhism insists life is suffering, so is to be endured. Hindus say our suffering is a result of sins of a previous life so bearing suffering is a way to atone for our sins..
But the churches are too busy preaching climate change and gay rights to preach such things. The only ones doing so are the "fundamentalists", and (ironically) Jordan Peterson...
IIRC drug that block it may be helpful for some kinds of chronic itch, rather than ouch.
In that case you need a copy of the German Commission E Monologues translated by the American Botanical Society. That has the reference studies listed with each “natural” remedy.
Approved are efficacious. Unapproved are not. Unlike doctors here, herbs are part of medical training in Germany.
I have always heard that if you have REAL pain, the opioids will not get you addicted..................
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