Faculty of Medicine and Health, The University of Sydney, Sydney, Australia (B.S.W., J.P.-O., A.G., S.E., C.A., S.N.M, M.J.C., R.J.V., S.A.M.) and School of Mathematical and Physical Sciences, University of Technology, Sydney, Australia (S.S., T.R.).
Faculty of Medicine and Health, The University of Sydney, Sydney, Australia (B.S.W., J.P.-O., A.G., S.E., C.A., S.N.M, M.J.C., R.J.V., S.A.M.) and School of Mathematical and Physical Sciences, University of Technology, Sydney, Australia (S.S., T.R.)
J Pharmacol Exp Ther. 2022 Sep;382(3):246-255. doi: 10.1124/jpet.122.001265. Epub 2022 Jul 2.
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--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--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--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--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--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.
脊髓甘氨酸能信号转导的改变是疼痛慢性化的一个特征。通过抑制甘氨酸转运体（GlyT）-2 使这些变化正常化是一种很有前途的治疗策略。然而，现有的 GlyT2 抑制剂（例如 ORG25543）受到治疗窗口狭窄和严重的剂量限制副作用（如惊厥）的限制，因此不太适合临床开发。在这里，腹腔内给予油酰--赖氨酸，一种基于脂质的 GlyT2 抑制剂，在急性（热板）、炎症（完全弗氏佐剂）和慢性神经病理性（慢性缩窄性损伤）疼痛的小鼠模型中进行了表征。副作用也通过数字评分、惊厥评分、运动协调障碍（转棒）和呼吸抑制（全身 plethysmography）进行了评估。油酰--赖氨酸对慢性神经病理性疼痛产生了近乎完全的抗痛觉过敏作用，但对炎症或急性疼痛没有抗痛觉过敏/镇痛作用。在峰值镇痛剂量 30mg/kg 时，没有观察到副作用。在最高剂量 100mg/kg 时，在数字评分上观察到轻微的副作用，但没有惊厥。这些结果与 ORG25543 形成鲜明对比，ORG25543 仅在 50mg/kg 的致死/接近致死剂量下，才能使痛觉过敏评分降低不到 50%。在这个剂量下，ORG25543 在数字评分上引起了最大的副作用和严重的惊厥。油酰--赖氨酸（30mg/kg）没有引起任何呼吸抑制，这是阿片类药物的一个有问题的副作用。这些结果表明，油酰--赖氨酸在小鼠中安全有效地逆转了神经病理性疼痛，并为甘氨酸在慢性疼痛中相对于急性或短期疼痛条件的独特作用提供了证据。 意义陈述：部分抑制甘氨酸转运体（GlyT）-2 通过恢复丢失的甘氨酸能功能可以缓解慢性疼痛。新型脂质基 GlyT2 抑制剂 ol--lys 安全有效地缓解神经病理性疼痛，但不能缓解炎症性或急性疼痛。GlyT2 抑制剂的临床应用可能更适合于慢性神经病理性疼痛，而不是其他疼痛病因。
