Peripheral Administration of Selective Glycine Transporter-2 Inhibitor, Oleoyl-_D-Lysine, Reverses Chronic Neuropathic Pain but Not Acute or Inflammatory Pain in Male Mice

Abstract

Aberrations in spinal glycinergic signalling are a feature of pain chronification. Normalising these changes by inhibiting glycine transporter-2 (GlyT2) is a promising treatment strategy.However, existing GlyT2 inhibitors e.g. ORG25543 are limited by narrow therapeutic windows and severe dose-limiting side effects such as convulsions, and are therefore poor candidates for clinical development. Here, intraperitoneally administered oleoyl-D -lysine, a lipid-based GlyT2 inhibitor, was characterised in mouse models of acute (hotplate), inflammatory (CFA) and chronic neuropathic (CCI) pain. Side effects were also assessed on a numerical rating score, convulsions score, for motor incoordination (rotarod) and for respiratory depression (whole body plethysmography). Oleoyl-D -lysine produced near complete anti-allodynia for chronic neuropathic pain but no anti-allodynia/analgesia in inflammatory or acute pain. No side effects were seen at the peak analgesic dose, 30 mg/kg. Mild side effects were observed at the highest dose, 100 mg/kg, on the numerical rating score, but no convulsions. These results contrasted markedly with ORG25543, which reached less than 50% reduction in allodynia score only at the lethal/near-lethal dose of 50 mg/kg. At this dose, ORG25543 caused maximal side effects on the numerical rating score and severe convulsions. Oleoyl-D -lysine (30 mg/kg) did not cause any respiratory depression, a problematic side effect of opiates. These results show the safe and effective reversal of neuropathic pain in mice by oleoyl-D -lysine and provide evidence for a distinct role of glycine in chronic pain over acute or short-term pain conditions.

Excitatory and inhibitory neuronal signaling in inflammatory and diabetic neuropathic pain

“…This process involves production of prostaglandin E2 (PGE2) by microglia, that leads to the activation of neuronal EP2 receptors and cyclic AMP-dependent protein kinase A (Cantaut-Belarif et al 2017 ). The role of GlyRs in chronic pain has been reviewed recently (Imlach 2017 ) and the importance of glycinergic signaling is further underlined by the fact that inhibition of GlyT2 glycine transporters alleviates chronic (but not acute) pain (Wilson et al 2022 ).

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