Project

Discipline

Pain; Spinal Cord; GABA; Glycine; Synaptic inhibition; Hyperalgesia; Slice; Electrophysiology; Animal model

Lead
Lay summary
About 20% of the general European population suffer from chronic pain. In almost two thirds of these patients, currently available pain killers (analgesic medications) provide either only unsatisfactory pain relief or cause treatment limiting side-effects. The development of novel analgesic drugs is therefore an urgent medical need. Fulfilling this need depends crucially on a better understanding of the biological basis of chronic pain. It is meanwhile generally accepted that chronic pain states are to a large extend due to an abnormal processing of pain stimuli and of other sensory stimuli in the sensory part (dorsal horn) of the spinal cord. There is increasing consensus that diminished synaptic inhibition in the spinal dorsal horn is a major contributor to chronic pain syndromes of various origins. Restoring synaptic inhibition in the spinal dorsal horn through drugs acting on the two major classes of inhibitory neurotransmitter receptors in the spinal cord, the gamma-amino butyric acid (GABA-A) receptors and strychnine-sensitive glycine receptors, should therefore be a promising strategy for the treatment of chronic pain. In the case of the GABA-A receptors we have already identified the relevant GABA-A receptor isoforms and are focussing on the site of their action within different parts of the central nervous system. While the molecular basis of drug interactions with GABA-A receptors has been carefully studied since many years, much less is known about similar possibilities at glycine receptors. We use here cannabinoid-derived molecules to identify parts of the glycine receptor molecule suitable for drug interactions. Both project parts use electrophysiological experiments in cell cultures and spinal cord slices, and behavioural testing in rodent models of chronic pain to define molecular targets for the development of novel analgesic drugs particularly useful for the treatment of chronic pain.

Direct link to Lay Summary

Last update: 21.02.2013

Active participation

Communication	Title	Media	Place	Year

Title	Year

Number	Title	Start	Funding scheme

Chronic pain constitutes a major medical and socio-economical problem worldwide. In particular chronic neuropathic pain often resists current medial treatment. It is meanwhile generally accepted that central pain sensitizing processes in the spinal cord dorsal horn are to a large extent responsible for many chronic pain syndromes. Within the last years it has become increasingly clear that a loss of spinal fast synaptic inhibition, normally provided by gamma-aminobutyric acid (GABA)ergic and glycinergic interneurons, is a key event in the generation and maintenance of pathological pain of inflammatory and neuropathic origin. A potentiation of the action of GABA and/or glycine at their dorsal horn receptors should therefore constitute a rational therapeutic strategy. We could indeed demonstrate that different forms of increased pain sensitivity can be normalized through a facilitation of spinal GABA-A receptor activation and could identify the GABA-A receptor isoforms responsible for this spinal antihyperalgesic action. Subproject A of this research proposal focuses on a better understanding of this GABA-A receptor-mediated antihyperalgesia and on the identification of strategies to restore inhibition in the sensitized spinal cord. Subproject B focuses on strychnine-sensitive glycine receptors, the other class of inhibitory neurotransmitter receptors in the spinal dorsal horn and investigates mechanisms and functional significance of their modulation by lipid signaling molecules. In subproject C, the function of a particular type of interneuron (protein kinase C-gamma positive interneurons) in the spinal dorsal horn shall be addressed through genetic ablation studies. It is believed that these neurons are critically involved in the generation of certain pain states in particular after nerve damage, yet this function has not been demonstrated directly yet. In all three subprojects an integrative approach is used with combines pharmacological, behavioral and electrophysiological experiments in genetically engineered mice.