Departments of Pharmacological Sciences (I.G., A.G., L.A.D.) and Psychiatry (L.A.D.), and Nash Family Department of Neuroscience (L.A.D.), Icahn School of Medicine at Mount Sinai, New York, New York; UCSF Weill Institute for Neurosciences, Department of Neurology, Neuroscience Graduate Program, University of California, San Francisco, California (E.B.M.); and Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York (L.D.F.).
Departments of Pharmacological Sciences (I.G., A.G., L.A.D.) and Psychiatry (L.A.D.), and Nash Family Department of Neuroscience (L.A.D.), Icahn School of Medicine at Mount Sinai, New York, New York; UCSF Weill Institute for Neurosciences, Department of Neurology, Neuroscience Graduate Program, University of California, San Francisco, California (E.B.M.); and Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York (L.D.F.)
Mol Pharmacol. 2024 Oct 17;106(5):240-252. doi: 10.1124/molpharm.124.000947.
Ketamine is a glutamate receptor antagonist that was developed over 50 years ago as an anesthetic agent. At subanesthetic doses, ketamine and some metabolites are analgesics and fast-acting antidepressants, presumably through targets other than glutamate receptors. We tested ketamine and its metabolites for activity as allosteric modulators of opioid receptors expressed as recombinant receptors in heterologous systems and with native receptors in rodent brain; signaling was examined by measuring GTP binding, -arrestin recruitment, MAPK activation, and neurotransmitter release. Although micromolar concentrations of ketamine alone had weak agonist activity at opioid receptors, the combination of submicromolar concentrations of ketamine with endogenous opioid peptides produced robust synergistic responses with statistically significant increases in efficacies. All three opioid receptors (, , and ) showed synergism with submicromolar concentrations of ketamine and either methionine-enkephalin (Met-enk), leucine-enkephalin (Leu-enk), and/or dynorphin A17 (Dyn A17), albeit the extent of synergy was variable between receptors and peptides. -ketamine exhibited higher modulatory effects compared with -ketamine or racemic ketamine, with ∼100% increase in efficacy. Importantly, the ketamine metabolite 6-hydroxynorketamine showed robust allosteric modulatory activity at opioid receptors; this metabolite is known to have analgesic and antidepressant activity but does not bind to glutamate receptors. Ketamine enhanced potency and efficacy of Met-enkephalin signaling both in mouse midbrain membranes and in rat ventral tegmental area neurons as determined by electrophysiology recordings in brain slices. Taken together, these findings support the hypothesis that some of the therapeutic effects of ketamine and its metabolites are mediated by directly engaging the endogenous opioid system. SIGNIFICANCE STATEMENT: This study found that ketamine and its major biologically active metabolites function as potent allosteric modulators of , , and opioid receptors, with submicromolar concentrations of these compounds synergizing with endogenous opioid peptides, such as enkephalin and dynorphin. This allosteric activity may contribute to ketamine's therapeutic effectiveness for treating acute and chronic pain and as a fast-acting antidepressant drug.
氯胺酮是一种谷氨酸受体拮抗剂，它在 50 多年前被开发为一种麻醉剂。在亚麻醉剂量下，氯胺酮及其一些代谢物具有镇痛和快速抗抑郁作用，可能是通过谷氨酸受体以外的靶点。我们测试了氯胺酮及其代谢物作为表达为异源系统重组受体和啮齿动物脑内天然受体的阿片受体的变构调节剂的活性；通过测量 GTP 结合、 -arrestin 募集、MAPK 激活和神经递质释放来检查信号转导。尽管单独使用微摩尔浓度的氯胺酮对 阿片受体具有微弱的激动活性，但亚微摩尔浓度的氯胺酮与内源性阿片肽联合使用可产生强大的协同反应，效力显著增加。所有三种阿片受体（ 、 和 ）均与亚微摩尔浓度的氯胺酮和甲硫氨酸脑啡肽（Met-enk）、亮氨酸脑啡肽（Leu-enk）和/或强啡肽 A17（Dyn A17）协同作用，尽管受体和肽之间的协同作用程度不同。与 -ketamine 或外消旋氯胺酮相比， -ketamine 表现出更高的调节作用，效力增加约 100%。重要的是，氯胺酮代谢物 6-羟基去甲氯胺酮在 阿片受体上表现出强大的变构调节活性；这种代谢物已知具有镇痛和抗抑郁作用，但不与谷氨酸受体结合。氯胺酮增强了 Met-enkephalin 在小鼠中脑膜和大鼠腹侧被盖区神经元中的信号转导的效力和效力，这是通过脑切片中的电生理学记录确定的。总的来说，这些发现支持了这样一种假设，即氯胺酮及其代谢物的一些治疗作用是通过直接参与内源性阿片系统来介导的。
本研究发现，氯胺酮及其主要生物活性代谢物作为 、 、 和 阿片受体的有效变构调节剂，这些化合物的亚微摩尔浓度与内源性阿片肽（如脑啡肽和强啡肽）协同作用。这种变构活性可能有助于氯胺酮治疗急性和慢性疼痛以及快速抗抑郁药物的治疗效果。
