PhD Scientific Days 2021

PH_II_L: Pharmaceutical Sciences II. Lectures

Glycin transoporter inhibitors: an emerging novel therapeutic option in the treatment of neuropathic pain

Text of the abstract

Introduction: Growing data on the analgesic effect of glycine transporter (GlyT) -1 or -2 inhibitors have been reported, however concerns regarding their side effects were raised. At present there is no available data on the combination of GlyT inhibitors in this regard.
Aims: Our primary goal was to assess the analgesic efficacy and possible motor side effects of GlyT1 (NFPS) and GlyT2 (ORG-25543) inhibitors in combination. Next, we aimed to elaborate on their impact on the amount of glycine and L-glutamate in the cerebrospinal fluid (CSF) and spinal cord tissue.
Method: Male Wistar rats (150-250g) underwent partial ligation of the sciatic nerve in order to induce a mononeuropathic state. Neuropathic animals were treated subcutaneously with NFPS, ORG-25543, or a combination of subanalgesic doses of the two agents. Mechanical allodynia was measured with dynamic plantar aesthesiometer, and the motor function of the animals was determined by Rotarod test. Spinal cord and CSF glycine and L-glutamate levels were quantified by capillary electrophoresis. Possible G-protein activating effect of the test compounds was investigated using GTPγS bindig assay.
Results: Neither NFPS nor ORG-25543 alone showed acute antiallodynic effect at doses of 1 or 2 mg/kg, respectively. NFPS or ORG-25543 produced analgesia at a dose of 4 mg/kg following acute administration. Next, co-treatment with subanalgesic doses of NFPS and ORG-25543 produced an acute analgesic effect. NFPS but not ORG-25543 showed analgesia after 4 days of treatment at doses of 1 or 2 mg/kg respectively. No motor dysfunction has been detected following these treatments. In the cerebrospinal fluid of neuropathic animals L-glutamate levels increased significantly. Combination therapy resulted in a significant increase in CSF glycine levels. Test compounds failed to activate G-proteins in the spinal cord.
Conclusion: To the best of our knowledge herein we demonstrated an augmented analgesia by combining GlyT-1 and -2 inhibitors for the first time. Involvement of the spinal glycinergic system in the perceived antiallodynic effect can be presumed. Combination of GlyT inhibitors may be an appropriate strategy for the treatment of neuropathic pain exploiting the augmented analgesic effect without significant side effects.

University and Doctoral School

Semmelweis University, Doctoral School of Pharmaceutical Sciences