Functional role and therapeutic potential of the glycine transporter GlyT1 in chronic pain
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
The treatment of pathological pain is despite intense research clinically still challenging. In many cases the treatment does not result in sufficient pain relieve and in addition the treatment compliance is often compromised by side effects of the medication that has a major impact on the patient quality of life. Thus new treatment approaches are urgently required. Here facilitation of glycinergic neurotransmission, that has been shown to be involved in the processing of pain related signals in the dorsal horn of spinal cord appears promising. In this project we could demonstrate that the GlyT1 specific inhibitor Bitopertin ameliorates the hyperreactivity in response to mechanical and thermal stimuli in animal models for neuropathic and inflammatory pain, consistent with an antiallodynic and antihyperalgesic effect of the drug. This effect was dose dependent and could be maintained for at least 4 weeks. Since Bitopertin has been already extensively tested in humans and has been shown to be well tolerated with only minor side effects, testing of Bitopertin in humans in the context of pain appears to be promising. To elucidate the precise mechanism how Bitopertin ameliorates we used an acute cell type specific loss of function approach, by unilateral inactivating GlyT1 expression in neurons or glial cells of the dorsal horn by Lenti virus mediated expression of Cre recombinase in mice carrying a Cre sensitive GlyT1 allele. Her we could show, that expression of Cre recombinase in glial cells but not neuron resulted in a significant reduction of GlyT1 immunreactivity within the dorsal horn of spinal cord. This inactivation of GlyT1 expression did not result in any detectable change in the reaction thresholds to mechanical or thermal stimuli, suggesting that GlyT1 inactivation does not result in any changes in sensory information processing. In animals that received previous to the virus mediated GlyT1 inactivation a chronic constriction of the sciatic (CCI) never, however, inactivation of GlyT1 in glial cells but not neuron resulted in a marked reduction of the CCI induced hyperreactivity, suggesting that the behavioural effects observed after Bitopertin application are at least in part caused by inhibition of glial GlyT1 in the dorsal horn. Taken together our data support the idea that GlyT1 inhibition might be a valuable new strategy for the treatment of pathological pain syndroms like neuropathic pain.
Publications
- (2018) The GlyT1 Inhibitor Bitopertin Ameliorates Allodynia and Hyperalgesia in Animal Models of Neuropathic and Inflammatory Pain. Front. Mol. Neurosci. 10:438
Armbruster A, Neumann E, Kötter V, Hermanns H, Werdehausen R and Eulenburg V
(See online at https://doi.org/10.3389/fnmol.2017.00438) - (2021) GlyT1 encephalopathy: Characterization of presumably disease causing GlyT1 mutations. Neurochem Int 139:104813
Hauf K, Barsch L, Bauer D, Buchert R, Armbruster A, Frauenfeld L, Grasshoff U, Eulenburg V
(See online at https://doi.org/10.1016/j.neuint.2020.104813) - (2022) Synergistic Control of Transmitter Turnover at Glycinergic Synapses by GlyT1, GlyT2, and ASC-1. Int J Mol Sci. 2022 Feb 25;23(5):2561
Eulenburg V, Hülsmann S
(See online at https://doi.org/10.3390/ijms23052561)
