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Gene discovered that affects sensitivity to pain

Interview with Prof. Irmgard Tegeder from the ICNF

Pain and sensitivity to pain belong to everyday experiences for every person. Prof. Dr. Irmgard Tegeder from the ICNF, who works at the Institute for Clinical Pharmacology at the University Clinic Frankfurt, could show in a report published in Nature Medicine that a specific gene variant in humans affects not only the sensitivity to direct (acute) pain in (healthy) people, but also the risk of chronic pain, for example following a spinal disc operation.

About a quarter of the population have this pain protecting gene variant. The carriers, in comparison to non-carriers, show reduced BH4 production in the presence of inflammation. BH4 is an enzyme helper factor essential for the generation of signal substances for the nervous system and nitrogen oxide. The study by Prof. Tegeder identified a genetic component in the risk of people developing neuropathic pain. The causes of neuropathic pain include traumatic or inflammatory damage to periphery and central nerves. It is often difficult to treat.

In an interview with our ICNF Newsletter editor Nicola A. Mögel, Prof. Tegeder describes her latest research. The interview took place on February 8, 2008.

Editor: Congratulations on your paper being published in the renowned scientific journal Nature Medicine. Your work focuses on reaction pathways in the induction of pain. What does this mean exactly?

Tegeder: Many factors play a role in influencing the induction of pain. We happened to investigate a possible signal pathway that seems to be very important. What is interesting is that there are certain people who feel less pain or respond better to surgical treatment of neuropathic pain, or react less to inflammatory pain, due to this genetic variability (Tegeder et al., 2006; Tegeder et al., 2008).

In these people the signal is not so strongly activated as in other people. This is a form of genetic protection. However, this protection doesn’t work to the same extent as taking a painkiller, an analgesic. But one can say that it protects from chronic pain, although not completely of course.

Ed.: You are talking about a genetic factor for pain sensitivity. Could this be tested before surgery?

Tegeder: This has not been carried out as yet. The article was only published in Nature Medicine at the end of 2006, and the connection only discovered shortly before that. Now, since our latest analyses have shown that this genetic variant not only influences the risk of chronic pain, but also cardiovascular risks (Antoniades et al., 2008), this will increase interest in a diagnostic test.

At the beginning of 2007, we published a diagnostic test (screening assay) for this genetic variant (Lotsch et al., 2007). This test could be used during diagnosis to estimate the individual risk of a patient who is, for example, facing surgery where a relatively high risk of nerve injury is expected. This means that in the future, by using diagnostic tests (screenings), physicians would be in the position to recognize early on any patients with a high risk of pain, and then quickly start intensive treatment.

Ed.: With your publication in Nature Medicine you have proved that your research is at the forefront in the world. With which international universities and research establishments do you have scientific collaborations?

Tegeder: I started this project at the University of Harvard (Boston). After I moved to Frankfurt I continued to collaborate closely with Clifford Woolf from the Neural Plasticity Research Group at the Massachusetts General Hospital and Harvard Medical School. In connection with aspects concerning the heart and blood vessels we cooperate in Frankfurt with Keith Channon from the Cardiovascular Research Initiative at the University of Oxford (UK). We have close scientific contacts with other colleagues in the USA, such as William Maixner from the University of North Carolina.

Quite recently, we established contact with William D. Snider from the Neuroscience Center at the University of North Carolina in connection with a planned exchange of mice. Our aim is to switch off the gene involved in a tissue specific manner, i.e. not in general, but only in neurons important for transmitting pain. To do this we are using so-called knockout mice. These are mice where a specific gene is removed in order to find out what function this gene performs.

Ed.: Where do you expect practical applications for your discovery?

Tegeder: While deciding on a therapeutic application still lies in the distant future, a diagnostic application is quite within the realms of possibility. Our screening assay could be introduced into the clinic with relatively little effort. We have patented our quick test and have already had enquiries from interested commercial parties.

Ed.: Thank you very much for taking the time to report on your work.

List of publications referred to by Prof. Tegeder

Antoniades C, Shirodaria C, Van Assche T, Cunnington C, Tegeder I, Lötsch J, Guzik TJ, Leeson P, Diesch J, Tousoulis D, Stefanadis C, Costigan M, Woolf CJ, Alp NC, Channon KM (2008) GCH-1 Haplotype Determines Vascular and Plasma Biopterin Availability in Coronary Artery Disease: Effects on Vascular Superoxide Production and Endothelial Function. J Am Coll Cardiol (in press).

Lotsch J, Belfer I, Kirchhof A, Mishra BK, Max MB, Doehring A, Costigan M, Woolf CJ, Geisslinger G, Tegeder I (2007) Reliable Screening for a Pain-Protective Haplotype in the GTP Cyclohydrolase 1 Gene (GCH1) Through the Use of 3 or Fewer Single Nucleotide Polymorphisms. Clin Chem 53:1010-1015.

Tegeder I, Adolph J, Haeussler A, Grundei IN, Kirchhof A, Doehring A, Schmidt H, Woolf CJ, Geisslinger G, Lotsch J (2008) Further evidence for reduced acute nociceptive pain and hyperalgesia and in homozygous carriers of a “pain-protective” GTP cyclohydrolase haplotype. Eur J Pain (in press).

Tegeder I, Costigan M, Griffin RS, Abele A, Belfer I, Schmidt H, Ehnert C, Nejim J, Marian C, Scholz J, Wu T, Allchorne A, Diatchenko L, Binshtok AM, Goldman D, Adolph J, Sama S, Atlas SJ, Carlezon WA, Parsegian A, Lotsch J, Fillingim RB, Maixner W, Geisslinger G, Max MB, Woolf CJ (2006) GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat Med 12:1269-1277.


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