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

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.

Pharmacological Evidence on Augmented Antiallodynia Following Systemic Co-Treatment with GlyT-1 and GlyT-2 Inhibitors in Rat Neuropathic Pain Model

“…Our results to amelioration of chronic NP are in accordance with other studies indicating that GlyT-1 or 2 inhibitors attenuate NP in rodents [ 6 , 7 , 23 , 25 , 26 ]. As mentioned above, GlyT-1 and 2 play crucial roles in the regulation of glycinergic inhibitory neurotransmission, and drugs that affect these transporters are able to affect systems operated by glycine.…”

“…Indeed, NFPS failed to show acute antiallodynic action, but it produced antiallodynic effect upon chronic treatment. Armbruster and coworkers showed that bitopertin, a GlyT-1 inhibitor, did produce antiallodynic effect following acute treatment in mice [ 23 ]. They have also proved that long-term treatment produces antiallodynic effect without noticeable side effects.…”

“…They have also proved that long-term treatment produces antiallodynic effect without noticeable side effects. The same group also reported on the acute antiallodynic effect of bitopertin (1 mg/kg) in CCI-evoked neuropathy in rats after subcutaneous or oral administration [ 23 ].…”

Comparative Pro-cognitive and Neurochemical Profiles of Glycine Modulatory Site Agonists and Glycine Reuptake Inhibitors in the Rat: Potential Relevance to Cognitive Dysfunction and Its Management

“…In addition, D-cycloserine and other glycine site ligands may improve social cognition in ASDs and genetically related Rett syndrome [115,116]. Other indications under consideration include drug abuse [117], amyotrophic lateral sclerosis [22], chronic pain [118] and facilitation of psychosocial-cognitive behavioural therapies for anxiety disorders [119]. potential conflict of interest.…”

Development and validation of a sensitive HPLC-HESI-MS/MS method for quantitative determination of bitopertin in rat and marmoset plasma

“…Bitopertin is a highly selective GlyT1 inhibitor that underwent several clinical trials, notably for the treatment of negative symptoms associated with schizophrenia (Bugarski-Kirola et al, 2017;Hirayasu et al, 2016;Kantrowitz et al, 2018;Rofail et al, 2016), obsessive-compulsive disorder (Roche, 2012) and β-thalassaemia (Roche, 2017;Taher et al, 2018). Moreover, recent pre-clinical studies suggested that bitopertin could have a therapeutic potential at managing neuropathic pain and improving cognition (Armbruster et al, 2018;Castner et al, 2014).…”