Yves De Koninck’s team shows that chronic pain depends on a cellular disorder that can be corrected
Researchers from the Faculty of Medicine of Université Laval have just taken a step towards the development of a new class of drugs to relieve chronic pain. Yves De Koninck , from the Institut universitaire de santé mentale de Québec, and 18 other researchers report in the latest issue of Nature Medicine that they have identified the mechanism responsible for this neurological disorder and are able to restore its functioning by the administration of a molecule designed for this purpose.
Under normal conditions, signals received by our bodies generate nerve impulses that are carried by nerve cells to the spinal cord. From there they are transmitted to the brain where they are decoded. “When we hurt our foot or our hand, it is in the head that the pain is felt ,” says Yves De Koninck. In the case of the transmission of a pain signal, there is a system in the spinal cord that determines whether the signal is relayed to the brain or not. The hypersensitivity of people suffering from chronic pain is thought to be due to a defect in the repression mechanism of pain signal transmission in the spinal cord. For this reason, normal sensory stimulation can result in the perception of severe pain.
The researcher attributes this imbalance to the loss of a protein (KCC2 ) in the membrane of certain nerve cells in the spinal cord. This protein is responsible for pumping chloride ions to the outside of nerve cells. “By maintaining a low concentration of chloride, it allows the inhibition of nerve signals”, said De Koninck. “In people with chronic pain, this pump reverses the normal flow of ions which makes the neurons of the spinal more excitable. “
According to this model, drugs that restore normal levels of KCC2 should restore the mechanism of inhibition of nerve signals. Researchers therefore began a search for molecules that promote the release of chloride ions in nerve cells while being non toxic, stable and able to travel to the spinal cord. They found one that stood out of the lot : CL -058 . Chemists associated with the team made 300 variants of this molecule. They were then tested in the laboratory to find the most effective.
Result ? One of these analogues resulted in a 40% reduction of chloride ions and helped restore normal functional response in hyperexcitable cells. It however has a downside: this molecule is rapidly degraded by the body, thereby reducing its value for therapeutic use in humans. “We have proven that our target was good, but the pharmacokinetics of this molecule was inadequate, says Dr. De Koninck . We have since found four or five promising new molecules and discussions are underway with a company to bring the work to the next step . “
The problems caused by the loss of KCC2 go far beyond the issue of chronic pain. The same imbalance is implicated in chronic stress, anxiety, autism, epilepsy, and even schizophrenia, says the researcher. ” This protein plays a central role in the homeostasis of chloride ions and in the stability of neural networks. “
Source of text:
Jean Hamann, Université Laval (in French)
Translation: CAN-ACN
Original research article:
Gagnon M, Bergeron MJ, Lavertu G, Castonguay A, Tripathy S, Bonin RP, Perez-Sanchez J, Boudreau D, Wang B, Dumas L, Valade I, Bachand K, Jacob-Wagner M, Tardif C, Kianicka I, Isenring P, Attardo G, Coull JA, De Koninck Y. Chloride extrusion enhancers as novel therapeutics for neurological diseases. Nat Med. 2013 Oct 6. doi: 10.1038/nm.3356. [Epub ahead of print] PubMed PMID: 24097188.
Yves De Koninck awarded the Jacques-Rousseau prize for multidisciplinarity by the Association francophone pour le savoir – ACFAS.
October 8th, 2013 – Yves De Koninck won the Jacques-Rousseau prize, awarded for multidisciplinarity. This award was established in 1980 in honor of Jacques Rousseau, botanist and ethnologist, to highlight the work of a person whose achievements have exceeded their area of expertise and have built new bridges between disciplines. This award recognizes the efforts of Dr. De Koninck to combine neuroscience and photonics over the last ten years. Since 2002, he has led numerous projects, including the creation of the Neurophotonics Centre which enabled a strengthening of link between the researchers of the Institut universitaire en santé mentale de Québec and the Centre d’optique, photonique et laser. His efforts allowed the power of photonics to be used for the study of the nervous system.
Source of Text: Université Laval (http://www.lefil.ulaval.ca/articles/trois-chercheurs-honores-par-acfas-35202.html)
Translation: CAN-ACN
Read more about this prize on the ACFAS website:
http://www.acfas.ca/prix-concours/prix-acfas/2013/prix-jacques-rousseau/yves-koninck
