Peripheral administration of selective GlyT2 inhibitor, oleoyl-D-lysine, is analgesic in a mouse model of neuropathic pain

Background and Purpose: Chronic pain is poorly managed by the limited treatment options currently available that act through a narrow range of mechanisms. The glycinergic system is fundamental in pain chronification and inhibiting glycine transporter-2 (GlyT2) is a promising new treatment strategy. However, development of GlyT2 inhibitors has seen limited success, with drugs such as ORG25543 having narrow therapeutic windows and causing severe dose-limiting side effects such as convulsions. Experimental Approach: The analgesic and side effect profiles of intraperitoneally administered oleoyl-D-lysine, a novel lipid-based GlyT2 inhibitor, were characterised. Analgesia was assessed via the von Frey test after chronic constriction injury. Side effects were scored on a numerical rating scale, convulsions score, Rotarod test and whole-body plethysmography for respiratory depression. Key Results: Oleoyl-D-lysine produced significant anti-allodynia, peaking at 1.5 h and with dose dependent increases in efficacy reaching a peak at 30 mg kg-1. At the highest dose, 100 mg kg-1, mild side effects were seen on the numerical rating score, but no convulsions were observed. These results contrasted with ORG25543, which produced limited analgesia, severe side effects and toxicity. The numerical rating score and Rotarod scores were maximal or near-maximal for ORG25543 and severe convulsions were caused. Oleoyl-D-lysine did not cause any respiratory depression, a problematic side effect of opiates. Conclusions and Implications: We show that lipid-based GlyT2-inhibitors are a viable and safe new class of analgesic compounds with oleoyl-D-lysine effectively reversing neuropathic pain in mice, with no side effects in the therapeutic range.