A study published in Nature Chemical Biology has opened up the possibility of being able to detect and treat of chronic pain. The scientists, who include Dr. Òscar Yanes (URV-CIBERDEM), have discovered by means of metabolomics that dimethylsphingosine (DMS) – a small molecule that is a subproduct of cell membrane degradation in the nervous system – accumulates in the spinal cord of rats suffering from neuropathic pain. Furthermore, DMS causes pain when it is injected into rats with no previous pain. The research opens the way to finding ways of inhibiting this molecule and to the future development of drugs.
Thousands of people suffer from chronic pain, but the reasons pain persists are unknown and there is no effective remedy. Now, and after 4 years work, a team of researchers has discovered one of the key elements that causes pain to persist: the DMS or dimethylsphingosine molecule. This is a small molecule that accumulates in the spinal cord of rats with neuropathic pain and that is caused by nerve degradation.
The researcher Òscar Yanes, who began the investigation at the Scripps Research Institute in San Diego (California, USA) and finished it at the Universitat Rovira i Virgili in Tarragona, explained that it was very difficult to find animals with chronic pain. In the end, he obtained two animal models by using rats. The process was as follows: the sciatic nerve ramifies into three at the level of the tibia. The researchers made an incision and cut one of these three nerves, which caused physical harm to the rats. They then closed the incision in the animal’s leg and the nerve regenerated itself over the course of the following days. After three weeks the nerve was fine but the animals were still in pain, which, according to Dr Yanes, “is similar to what can happen to us if we go to the doctor with chronic pain and see no change when he examines us internally”.
Pressure was applied to the rats’ legs resulted in pain, despite the nerve being fine. The investigators measured metabolites –small molecules- in the blood, in the spinal cord, and in the nerve itself, and found that when they compared rats with and without chronic pain, “there were large differences in the spinal cord just at the point where there is a connection to the nerve that transmits the information to the brain”. They discovered that metabolites resulting from the degradation of the nerve accumulated in a small part of the spinal cord where messages are received from the sciatic nerve and transmitted to the brain. “We proposed that the body was unable to eliminate these accumulated metabolites. We also found that when one of these compounds, DMS, was injected into the spinal cord of the healthy rats, these rats were in pain after a few hours.” The DMS lipid was known to exist, but it was not known that it is endogenous, that is, that it could be produced by the body. This finding was possible thanks to the mass-spectrometry techniques used in metabolomics, a new scientific discipline that is increasingly used to find biochemical markers and indicators of illnesses.
These compounds are associated with a metabolic pathway involving enzymes; that is, the proteins that transform these little molecules. “We have demonstrated that there is a metabolic pathway on which interventions can be made; that is, we show a cascade of reactions that in the future may be useful for locating inhibitors”. Yanes states that “if the enzymes that generate DMS could be blocked, it would be possible to reduce pain”. It has yet to be demonstrated whether the model can be extrapolated to all types of chronic pain, but until now virtually nothing has been known about this kind of pain at molecular level “and this is the first step” towards rectifying that.
According to Dr Yanes, the work could open up new research lines into pain associated with diabetes, which is the focus of the research carried out by the Metabolomics Platform of the URV and CIBERDEM. “We first need to see if the results can be extrapolated to humans” and to do so, it has to be established whether DMS accumulates in humans who suffer from chronic pain “or find an animal model of a diabetic mouse so that we can carry out similar research to that which has already been done.”
Dr Yanes’ idea is to look for some of these compounds in the blood of patients with chronic pain: “We now have the capacity to find markers, to try and quantify the pain and to provide tools to clinics that remove the need for patients to evaluate their pain by means of a test”. Another factor to be determined is where the pain comes from: “Now that we have established the metabolic pathway and which compounds accumulate, in the short term we need to look for these compounds in the blood or the cerebrospinal fluid because it is easier to develop drugs for these areas”.
The study was published in Nature Chemical Biology and was started in 2007 at the Scripps Research Institute at La Jolla in California. The study’s authors were coordinated by Gary Siuzak, professor at the Department of Chemistry and Molecular Biology at the institute. Òscar Yanes and the other main author of the article, Gary J. Patti, finished the research at different sites, on at the URV in Tarragona, and the other at Washington University (St. Louis, USA). Yanes is the main author of the article and is the researcher who started the study, took the samples, made the comparative analyses and found the DMS. He also coordinates the Metabolomics Platform (http://metabolomicsplatform.com/) from Tarragona and leads his own group (www.yaneslab.com). He participated in this research as a URV and CIBERDEM researcher.
Òscar Yanes is gained his doctorate in Biochemistry from the UAB. After four years of postdoctoral study as an associate researcher at the Scripps Research Institute in California, he returned to Catalonia last year to work at the URV because the university’s Metabolomics Platform provides the conditions he needs to carry out his research. He is currently a researcher and lecturer at the URV.
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