Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, H-1085 Budapest, Hungary.
Center for Pharmacology and Drug Research & Development, Semmelweis University, Üllői út 26., H-1085 Budapest, Hungary.
Int J Mol Sci. 2024 Oct 17;25(20):11136. doi: 10.3390/ijms252011136.
Opioid analgesic tolerance (OAT), among other central side effects, limits opioids' indispensable clinical use for managing chronic pain. Therefore, there is an existing unmet medical need to prevent OAT. Extrasynaptic N-methyl D-aspartate receptors (NMDARs) containing GluN2B subunit blockers delay OAT, indicating the involvement of glutamate in OAT. Glycine acts as a co-agonist on NMDARs, and glycine transporters (GlyTs), particularly GlyT-1 inhibitors, could affect the NMDAR pathways related to OAT. Chronic subcutaneous treatments with morphine and NFPS, a GlyT-1 inhibitor, reduced morphine antinociceptive tolerance (MAT) in the rat tail-flick assay, a thermal pain model. In spinal tissues of rats treated with a morphine-NFPS combination, NFPS alone, or vehicle-comparable changes in µ-opioid receptor activation, protein and mRNA expressions were seen. Yet, no changes were observed in GluN2B mRNA levels. An increase was observed in glycine and glutamate contents of cerebrospinal fluids from animals treated with a morphine-NFPS combination and morphine, respectively. Finally, GlyT-1 inhibitors are likely to delay MAT by mechanisms relying on NMDARs functioning rather than an increase in opioid efficacy. This study, to the best of our knowledge, shows for the first time the impact of GlyT-1 inhibitors on MAT. Nevertheless, future studies are required to decipher the exact mechanisms.
阿片类药物镇痛耐受（OAT），以及其他中枢副作用，限制了阿片类药物在治疗慢性疼痛方面的不可或缺的临床应用。因此，存在着预防 OAT 的未满足的医疗需求。包含 GluN2B 亚基的突触外 N-甲基-D-天冬氨酸受体（NMDAR）阻滞剂可延迟 OAT，表明谷氨酸参与了 OAT。甘氨酸作为 NMDAR 的协同激动剂，而甘氨酸转运体（GlyTs），特别是 GlyT-1 抑制剂，可能会影响与 OAT 相关的 NMDAR 途径。慢性皮下给予吗啡和 NFPS（一种 GlyT-1 抑制剂）可减少大鼠尾部闪烁试验（一种热痛模型）中的吗啡镇痛耐受（MAT）。在接受吗啡-NFPS 联合治疗、NFPS 单独治疗或载体治疗的大鼠脊髓组织中，观察到 µ-阿片受体激活、蛋白和 mRNA 表达的相似变化。然而，GluN2B mRNA 水平没有变化。在接受吗啡-NFPS 联合治疗和吗啡治疗的动物的脑脊液中，甘氨酸和谷氨酸含量分别增加。最后，GlyT-1 抑制剂可能通过依赖 NMDAR 功能而不是增加阿片类药物疗效的机制来延迟 MAT。据我们所知，这项研究首次显示了 GlyT-1 抑制剂对 MAT 的影响。然而，需要进一步的研究来阐明确切的机制。
