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As much as people may dislike pain, it is usually an important part of human existence. When a part of the body experiences a physiological change that potentially could be harmful or life-threatening, the brain is sent a signal – pain – from our nerves to ensure we react accordingly. In this context, pain is designed to be acute but unfortunately in many situations including healing and chronic disease, pain can last and may need to be managed.

Pain management can be localized to help certain areas but most management options are universal in that an oral medication is taken and a whole-body effect occurs. Examples of these medications are acetylsalicylic acid, acetaminophen, ibuprofen, and opioids. These tend to numb or dull pain signals rather than block them completely. In order to complete block the pain signals, one needs to look into the cell and find out what is occurring.

From basic research on the control of cellular energy production, Dr. Thomas Simmen has been able to find one of these mechanisms. Given that pain sensation requires controlled cellular energy production, he collaborated with Dr. Bradley Kerr in the Department of Anesthesiology and Pain Medicine. Based on these previous findings, Dr. Aislinn Maguire, a recently graduated student in the Kerr lab, has found a way to block that mechanism and, in effect, pain. They have published their findings in the journal, Anesthesiology.

But before the treatment can be introduced, one needs to understand how a nerve cell feels pain.  It comes down to an intricate pathway this that involves both the endoplasmic reticulum (ER) and the mitochondria. As Dr. Simmen’s group has shown, when the ER is stressed, it requires a significant increase in energy. It sends a signal to the energy-producer of the cell, the mitochondria, to start making more energy in the form of adenosine triphosphate or ATP. In most cells, this happens without us knowing about it. But when it happens in a nerve cell, it leads to a signal that is sent to the brain. That signal is what we call pain.   

The Cellular Source of Pain
Taken from the Cell Reports paper "The endoplasmic reticulum kinase PERK
interacts with the oxidoreductase ERO1 to metabolically adapt mitochondria." 

With all of this information in hand, which took years of experimentation between the Simmen and Kerr labs, the duo set to halt the signal between the ER and the mitochondria in the hopes of stopping that pain signal. They attempted this by blocking the signal sender, an enzyme known as ER Oxidoreductase 1 or ERO1. They performed their experiments in mice that were artificially triggered to sense pain.

The results were shocking or, to be more accurate, painless. The use of the blocker reduced the pain signals to the brain in such a way that the mice were in essence no longer feeling constant and troubling pain. The reductions could be seen both at the cellular level but also in the way the mice behaved. It was a complete turnaround.    

The results of this study provide a door to translate these findings from the animal model to the human although this has been attempted before with little success. However, the duo backed up their findings by showing the same ERO1 exists in human brain cells under conditions associated with chronic pain. They also performed a similar test on human nerve cells cultured in petri dishes and showed that the pain signals were indeed blocked.

Thanks to these findings, the team is currently developing a patent for the process and is looking for a path towards advancing their findings to a clinically proven pain therapeutic. They are in the first stages of their journey but know that increased support from funding and donations will assist them to reach their overall goal.