Assessment of the Anti-Allodynic and Anti-Hyperalgesic Efficacy of a Glycine Transporter 2 Inhibitor Relative to Pregabalin, Duloxetine and Indomethacin in a Rat Model of Cisplatin-Induced Peripheral Neuropathy.

Cisplatin, which is a chemotherapy drug listed on the World Health Organisation's List of Essential Medicines, commonly induces dose-limiting side effects including chemotherapy-induced peripheral neuropathy (CIPN) that has a major negative impact on quality of life in cancer survivors. Although adjuvant drugs including anticonvulsants and antidepressants are used for the relief of CIPN, analgesia is often unsatisfactory. Herein, we used a rat model of CIPN (cisplatin) to assess the effect of a glycine transporter 2 (GlyT2) inhibitor, relative to pregabalin, duloxetine, indomethacin and vehicle. Male Sprague-Dawley rats with cisplatin-induced mechanical allodynia and mechanical hyperalgesia in the bilateral hindpaws received oral bolus doses of the GlyT2 inhibitor (3-30 mg/kg), pregabalin (3-100 mg/kg), duloxetine (3-100 mg/kg), indomethacin (1-10 mg/kg) or vehicle. The GlyT2 inhibitor alleviated both mechanical allodynia and hyperalgesia in the bilateral hindpaws at a dose of 10 mg/kg, but not at higher or lower doses. Pregabalin and indomethacin induced dose-dependent relief of mechanical allodynia but duloxetine lacked efficacy. Pregabalin and duloxetine alleviated mechanical hyperalgesia in the bilateral hindpaws while indomethacin lacked efficacy. The mechanism underpinning pain relief induced by the GlyT2 inhibitor at 10 mg/kg is likely due to increased glycinergic inhibition in the lumbar spinal cord, although the bell-shaped dose-response curve warrants further translational considerations.