Peripheral administration of selective GlyT2 inhibitor, oleoyl-D-lysine,
is analgesic in neuropathic but not acute or inflammatory pain models in
Background and Purpose: Changes to spinal glycinergic signalling are a
feature of pain chronification. Normalising those 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.
Experimental Approach: Analgesic and side-effect properties of
intraperitoneally administered oleoyl-D-lysine, a lipid-based GlyT2
inhibitor, were characterised in mice. Analgesia was assessed in models
of chronic neuropathic and inflammatory pain via the von Frey test, and
acute nociception via hotplate. Side effects were scored via numerical
rating scale, convulsions score, the Rotarod test and whole-body
plethysmography for respiratory depression. Key Results: Oleoyl-D-lysine
produced significant analgesia/anti-allodynia in the model for chronic
neuropathic pain but not for chronic inflammatory or acute pain. No side
effects were seen at the peak analgesic dose, 30 mg kg-1. Mild side
effects were observed at the highest dose, 100 mg kg-1, in the numerical
rating score, but no convulsions. These results contrasted markedly with
ORG25543, which produced significant analgesia only at the lethal or
near-lethal dose of 50 mg kg-1. At this dose, ORG25543 caused severe
side effects on the numerical rating score, severe convulsions, and
Rotarod impairment. Oleoyl-D-lysine (30 mg kg-1) did not cause any
respiratory depression, a problematic side effect of opiates.
Conclusions and Implications: Oleoyl-D-lysine safely and effectively
reverses neuropathic pain in mice. GlyT2 inhibitors may be better suited
to treating pain of neuropathic origin over other pain aetiologies.