Neuroscience Graduate Program (J.G.Y., C.A.B., I.L.), Department of Pharmacology and Molecular Therapeutics (H.A.W., C.A.B., I.L.), and Department of Psychiatry (I.L.), Uniformed Services University, Bethesda, Maryland.
Neuroscience Graduate Program (J.G.Y., C.A.B., I.L.), Department of Pharmacology and Molecular Therapeutics (H.A.W., C.A.B., I.L.), and Department of Psychiatry (I.L.), Uniformed Services University, Bethesda, Maryland
J Pharmacol Exp Ther. 2022 Sep;382(3):256-265. doi: 10.1124/jpet.122.001278. Epub 2022 Jul 2.
Commonly used pain therapeutics, such as opioid medications, exert dangerous side effects and lack effectiveness in treating some types of pain. Ketamine is also used to treat pain, but side effects limit its widespread use. (2,6)-hydroxynorketamine (HNK) is a ketamine metabolite that potentially shares some beneficial behavioral effects of its parent drug without causing significant side effects. This study compared the profile and potential mechanisms mediating the antinociception activity of ketamine and (2,6)-HNK in C57BL/6J mice. Additionally, this study compared the reversal of mechanical allodynia by (2,6)-HNK with gabapentin in a model of neuropathic pain. Unlike the near-immediate and short-lived antinociception caused by ketamine, (2,6)-HNK produced late-developing antinociception 24 hours following administration. Pharmacological blockade of -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors with 2,3-dioxo-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX) prevented the initiation and expressionof (2,6)-HNK antinociception, suggesting the involvement of -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-dependent glutamatergic mechanisms in the pain reduction-like responses. Blockade of opioid receptors with naltrexone partially prevented the antinociceptive effect of ketamine but was ineffective against (2,6)-HNK. Furthermore, (2,6)-HNK did not produce dystaxia, even when tested at doses five times greater than those needed to produce antinociception, indicating a superior safety profile for (2,6)-HNK over ketamine. Additionally, (2,6)-HNK reversed mechanical allodynia in a spared nerve injury model of neuropathic pain with similar short-term efficacy to gabapentin (within 4 hours) while outperforming gabapentin 24 hours after administration. These findings support the further study of (2,6)-HNK as a potentially valuable agent for treating different types of pain and establish certain advantages of (2,6)-HNK treatment over ketamine and gabapentin in corresponding assays for pain. SIGNIFICANCE STATEMENT: The ketamine metabolite (2,6)-HNK produced antinociception in male and female mice 24 hours after administration via activation of AMPA receptors. The effects of (2,6)-HNK differed in time course and mechanism and presented a better safety profile than ketamine. (2,6)-HNK also reversed allodynia in SNI-operated animals within 4 hours of treatment onset, with a duration of effect lasting longer than gabapentin. Taken together, (2,6)-HNK demonstrates the potential for development as a non-opioid analgesic drug.
常用的止痛疗法，如阿片类药物，会产生危险的副作用，并且在治疗某些类型的疼痛方面效果不佳。氯胺酮也用于治疗疼痛，但副作用限制了其广泛应用。(2,6)-羟基去甲氯胺酮 (HNK) 是氯胺酮的一种代谢物，它可能具有与其母体药物相似的一些有益的行为效应，而不会引起明显的副作用。本研究比较了氯胺酮和 (2,6)-HNK 在 C57BL/6J 小鼠中镇痛活性的特征和潜在机制。此外，本研究比较了 (2,6)-HNK 在神经病理性疼痛模型中逆转机械性痛觉过敏的效果与加巴喷丁的效果。与氯胺酮引起的即刻和短暂的镇痛作用不同，(2,6)-HNK 在给药 24 小时后产生迟发性镇痛作用。用 2,3-二氧代-6-硝基-7-磺胺基苯并[f]喹喔啉 (NBQX) 阻断 -氨基-3-羟基-5-甲基-4-异恶唑丙酸 (AMPA) 受体，可阻止 (2,6)-HNK 镇痛作用的起始和表达，表明 -氨基-3-羟基-5-甲基-4-异恶唑丙酸受体依赖性谷氨酸能机制参与了疼痛减轻样反应。用纳曲酮阻断阿片受体可部分阻止氯胺酮的镇痛作用，但对 (2,6)-HNK 无效。此外，即使在测试剂量是产生镇痛作用所需剂量的五倍时，(2,6)-HNK 也不会产生运动失调，表明 (2,6)-HNK 的安全性优于氯胺酮。此外，(2,6)-HNK 在 spared nerve injury 模型中逆转机械性痛觉过敏，其短期疗效与加巴喷丁相似（在 4 小时内），而在给药后 24 小时的疗效优于加巴喷丁。这些发现支持进一步研究 (2,6)-HNK 作为治疗不同类型疼痛的潜在有价值的药物，并确定 (2,6)-HNK 在相应的疼痛测定中与氯胺酮和加巴喷丁相比具有某些优势。意义声明：氯胺酮代谢物 (2,6)-HNK 通过激活 AMPA 受体，在雄性和雌性小鼠给药 24 小时后产生镇痛作用。(2,6)-HNK 的作用在时程和机制上有所不同，且安全性优于氯胺酮。(2,6)-HNK 在 SNI 手术动物中也能在治疗开始后 4 小时内逆转痛觉过敏，作用持续时间长于加巴喷丁。总之，(2,6)-HNK 具有作为非阿片类镇痛药开发的潜力。
