Aberrations in spinal glycinergic signaling are a feature of
pain chronification. Normalizing these changes by inhibiting
glycine transporter (GlyT)-2 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 characterized in mouse models of acute (hot plate), inflammatory (complete
Freund's adjuvant), and chronic neuropathic (chronic constriction injury)
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 antiallodynia for chronic
neuropathic pain, but no antiallodynia/
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
glycine transporter (GlyT)-2 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.