Functional role and therapeutic potential of the glycine transporter GlyT1 in chronic pain

• Applicant: Professor Dr. Volker Eulenburg
• Subject Area: Cognitive, Systems and Behavioural Neurobiology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 324595044

The main function of pain perception is to protect organisms from damage caused by noxious stimuli. Maladaptive plasticity within the nociceptive system can result in allodynia and/or hyperalgesia. Under these conditions pain loses its protective role, and is considered as anautonomous disease in itself. Despite extensive suffering of affected patients and intense research over decades, the neuronal mechanisms leading to these chronic pain conditions pain are still only poorly understood and treatment options remain rather unsatisfying. In recent approaches, the restoration of inhibitory neurotransmission within the dorsal horn of spinal cord has been a major aim for the development of new treatment options for chronic pain conditions.The enhancement of GABAergic neurotransmission, however, has proven difficult in part due to the high abundance of GABAA receptors in higher brain regions that cause unfavourable side effects. Since glycinergic neurotransmission is largely restricted to caudal parts of the central nervous system, similar central side effects are not to be expected. Therefore, the glycinergic system seems to be a promising novel target for therapeutic approaches against chronic pain. We have shown previously that pharmacological reduction of the glycine transporter 1 (GlyT1) glycine uptake activity efficiently reduces the facilitated pain response in animal models of neuropathic as well as inflammatory pain. In this project we aim to elucidate the mechanisms how inhibition of GlyT1 ameliorates chronic pain by an interdisciplinary project combining molecular biological and histological as well as neurophysiological approaches.In detail, we plan to make use of a mouse line that carries a modified GlyT1 allele allowing the Cre recombinase mediated inactivation of GlyT1 expression. By stable transgenic or viral induced expression of Cre recombinase in mice of this mouse line we plan to obtain a cell type and/or regions specific GlyT1 deficiency. In these mice, we plan first to determine the consequences of GlyT1 deficiency on glycine dependent inhibitory and excitatory neurotransmission by an electrophysiological approach in dorsal horn neurons. Subsequently we plan to induce neuropathic or inflammatory pain conditions in these mice and determine the neuroplastic changes that accompany the chronification of pain, by biochemical, histological and electrophysiological methods. Comparison to wild-type animals will reveal the inpact of the respective GlyT1 population on the effects of Glyt1 active substances in the context of chonic pain. Taken together this project will provide new information on the cell type specific functions of GlyT1 within the spinal cord both under physiological conditions and under the influence of chronic pain. This will provide new insight on the mechanism by which substances acting on GlyT1 influence chronic pain.

• DFG Programme: Research Grants