Robert Klatt
A sunflower molecule suppresses pain without crossing the blood-brain barrier. In the future, the active ingredient could replace opioids, which are highly addictive and have severe side effects.
Vienna, Austria). Opioids, which are derivatives of the opium obtained from the opium poppy, bind to the μ-opioid receptor in the brain and nervous system and thereby suppress pain. Despite their negative effects such as the high risk of addiction and the risk of respiratory paralysis, opioids are still the most widely used active ingredient in medicine for the treatment of severe pain.
In order to enable the treatment of pain with fewer side effects, however, science is also looking for alternatives to opioids. Among other things, it was discovered that the poison of the puffer fish tetrodoxin and the penicillium species MST-MF667 obtained from mushrooms are suitable for the treatment of pain. Now researchers from the Institute of Pharmacology have MedUni Vienna identified another natural pain reliever in cooperation with the University of Queensland and Flinders University.
Kappa opioid receptor
According to their publication in Journal of Medicinal Chemistry Edin Muratspahic’s team concentrated on active ingredients that dock on the kappa opioid receptor (KOR). The effect is almost identical to the blocking of the μ-opioid receptor, i.e. it also suppresses pain, but does not cause any euphoric feelings and therefore does not trigger any risk of addiction. The problem is that active substances that bind to the kappa opioid receptor in the brain can lead to negative emotions, drowsiness and even hallucinations.
The scientists therefore looked for an active ingredient that does not cross the blood-brain barrier and only docks with the kappa opioid receptors in the body. As a basis for their research, the team used reports from traditional medicine that sunflower extract is suitable for treating pain and inflammation.
Peptide SFT-1 extracted from the sunflower
In the first step, the scientists therefore isolated the peptide SFT-1, one of the main components of the sunflower extract, and examined whether it binds to kappa opioid receptors. It turned out that the sunflower peptide actually binds to the receptor and thereby blocks signal transmission. In order to improve the effect even further, the scientists then modified the ring-shaped protein chain by inserting a piece of an endogenous KOR active ingredient into the peptide.
Helianorphine-19 as a new pain reliever
The result was the new active ingredient helianorphin-19, which cannot cross the blood-brain barrier but still docks effectively with the kappa receptor. “This peptide is extremely stable, highly potent and has a restrictive effect on the body periphery. Therefore, fewer of the typical side effects of opioids are to be expected when used, ”explains Christian Gruber. Administration of helianorphine-19 to humans would in principle be possible orally, because tests have shown that the molecule is insensitive to gastric acid.
Successful experiments with mice
In experiments with mice that had hypersensitive intestines, the scientists investigated how selectively helianorphine-19 works against pain. They found that helianorphine-19 inhibits the stretching of the intestine that is typical of pain. In contrast, the pain response remained unchanged in the control group that was not treated with the modified sunflower peptide.
An analysis of the selectivity of the active ingredient also gave positive results. Helianorphine-19 therefore only blocks the transmission of pain, but does not trigger the cascades of reactions that are responsible for the typical opioid side effects. This was confirmed by behavioral tests, in which no evidence whatsoever for an intoxicating effect of helianorphine-19 was found.
Use in inflammatory bowel diseases
According to the scientists, the results show that the modified sunflower peptide could serve as the basis for new drugs in the future. “This active ingredient turned out to be our top candidate as a possible new pain reliever, especially for pain in the gastrointestinal tract or in the peripheral organs,” explains Gruber. The application would be conceivable above all in inflammatory bowel diseases.
Journal of Medicinal Chemistry, doi: 10.1021/acs.jmedchem.1c00158
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