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.
Significance Statement Partially inhibiting GlyT2 can alleviate chronic pain by restoring lost glycinergic function. Novel lipid-based GlyT2 inhibitor, ol-D-lys, is safe and effective in alleviating neuropathic pain, but not inflammatory or acute pain. Clinical application of GlyT2 inhibitors may be better suited to chronic neuropathic pain over other pain aetiologies.
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