GABAergic pain control and analgesia- the role of spinal gamma1-containing GABAA receptors.

• Applicant: Dr. Elena Neumann
• Subject Area: Anaesthesiology
• Term: from 2016 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 298965697

Chronic pain is a major problem worldwide, which can severely impair patients` quality of life and ability to work. So far, that pain is often resistant to pharmacotherapy. Animal studies suggest that a loss of GABAergic and/ or glycinergic inhibition in the spinal cord contributes significantly to chronic pain states. Subtype-selective benzodiazepines, which enhance the activity of specific spinal GABAA receptors have been demonstrated to be antihyperalgesic in animal studies yet devoid of unwanted sedation or tolerance development. The latter are typical side-effects of classical benzodiazepines. Benzodiazepine-sensitive GABAA receptors are composed of two alpha-, two beta- and one gamma-subunit. There are several isoforms of each subunit. While alpha2-containing GABAA receptors (alpha2-GABAA receptors) are considered to mediate spinal antihyperalgesia to a large extent, alpha1-GABAA receptors, which mediate sedative effects of classical benzodiazepines do not contribute significantly in any of the pain models tested. Although the benzodiazepine binding site is formed by one alpha- and one gamma-subunit together, so far, the studies on antihyperalgesia relevant GABAA receptor subtypes focused almost exclusively on the different alpha-subunits. Even though that approach was successful different observations suggest that effect differences of benzodiazepine receptor agonists can not be explained completely by the diverse alpha-subunits. Different from most regions of the brain, preliminary data indicate that in the spinal cord also other gamma-subunits than the gamma2-subunit are expressed in a relevant amount. Therefore, the proposed project aims to study whether an antihyperalgesic effect of benzodiazepine binding site agonists can be achieved by targeting spinal GABAA receptors containing the gamma1- or gamma3-subunit, and whether their modulation can provide a therapeutic approach for the treatment of chronic pain. Thus, in vitro and in vivo studies on a molecular, cellular and systemic level are planned to be combined. In case non-gamma2-GABAA receptors contributed significantly to spinal benzodiazepine-mediated antihyperalgesia the development of drugs modulating these receptors would provide an additional possibility to selectively influence spinal GABAA receptors.

• DFG Programme: Research Fellowships
• International Connection: Switzerland
• Host: Professor Dr. Hanns Ulrich Zeilhofer