The GlyT1 Inhibitor Bitopertin Ameliorates Allodynia and Hyperalgesia in Animal Models of Neuropathic and Inflammatory Pain.

Anja Armbruster,Henning Hermanns,Volker Eulenburg,Elena Neumann,Robert Werdehausen,Valentin Kötter

doi:10.3389/fnmol.2017.00438

Abstract

Background: Chronic pain conditions are difficult to treat and the therapeutic outcome is frequently unsatisfactory. Changes in excitation/inhibition balance within the dorsal horn contribute to the establishment and persistence of chronic pain. Thus, facilitation of inhibitory neurotransmission is a promising approach to treat chronic pain pharmacologically. Glycine transporter 1 (GlyT1) plays an important role in regulating extracellular glycine concentrations. Aim of the present study therefore was to investigate whether the specific GlyT1 inhibitor bitopertin (RG1678; RO4917838) might constitute a novel treatment for chronic pain by facilitating glycinergic inhibition.Methods: Mechanical allodynia and thermal hyperalgesia were induced by chronic constriction injury of the sciatic nerve or carrageenan injections into the plantar surface of the hind paw in rodents. The effect of acute and long-term bitopertin application on the reaction threshold to mechanical and thermal stimuli was determined. General activity was determined in open field experiments. The glycine concentration in cerebrospinal fluid and blood was measured by HPLC.Results: Systemic application of bitopertin in chronic pain conditions lead to a significant increase of the reaction thresholds to mechanical and thermal stimuli in a time and dose-dependent manner. Long-term application of bitopertin effectuated stable beneficial effects over 4 weeks. Bitopertin did not alter reaction thresholds to stimuli in control animals and had no effect on general locomotor activity and anxiety but lead to an increased glycine concentration in cerebrospinal fluid.Conclusion: These findings suggest that inhibition of the GlyT1 by bitopertin represents a promising new approach for the treatment of chronic pain.

Highlights

Chronic pain is defined as a long-lasting pain which outlasts the period of healing of the original noxious stimulus (Kuner and Flor, 2016)
To test if bitopertin ameliorates the facilitated pain response in animal models for chronic pain, neuropathic pain was induced in mice by constriction injury (CCI)
Sensory testing revealed the development of allodynia and hyperalgesia within 10 days after CCI on the ipsilateral side

Summary

Introduction

Chronic pain is defined as a long-lasting pain which outlasts the period of healing of the original noxious stimulus (Kuner and Flor, 2016). Chronic pain associated by inflammation was shown to depend on a protein kinase A (PKA)-dependent downregulation of predominantly glycine receptor α3 mediated glycinergic neurotransmission (Harvey et al, 2004), whereas neuropathic pain is independent of these processes (Hosl et al, 2006). Consistent with these differences the therapeutic strategies for the treatment of the assorted chronic pain modalities varie. Bitopertin did not alter reaction thresholds to stimuli in control animals and had no effect on general locomotor activity and anxiety but lead to an increased glycine concentration in cerebrospinal fluid. Conclusion: These findings suggest that inhibition of the GlyT1 by bitopertin represents a promising new approach for the treatment of chronic pain

Methods

Results

Conclusion