Department of Small Animal Diseases with Clinic, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Nowoursynowska 166, 02-787 Warsaw, Poland.
Department of Experimental Genomics, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Postępu 36A, 05-552 Jastrzębiec, Poland.
Int J Mol Sci. 2024 Jun 26;25(13):6978. doi: 10.3390/ijms25136978.
Currently, pharmacotherapy provides successful seizure control in around 70% of patients with epilepsy; however, around 30% of cases are still resistant to available treatment. Therefore, effective anti-epileptic therapy still remains a challenge. In our study, we utilized two mouse lines selected for low (LA) and high (HA) endogenous opioid system activity to investigate the relationship between down- or upregulation of the opioid system and susceptibility to seizures. Pentylenetetrazole (PTZ) is a compound commonly used for kindling of generalized tonic-clonic convulsions in animal models. Our experiments revealed that in the LA mice, PTZ produced seizures of greater intensity and shorter latency than in HA mice. This observation suggests that proper opioid system tone is crucial for preventing the onset of generalized tonic-clonic seizures. Moreover, a combination of an opioid receptor antagonist-naloxone-and a GABA receptor agonist-diazepam (DZP)-facilitates a significant DZP-sparing effect. This is particularly important for the pharmacotherapy of neurological patients, since benzodiazepines display high addiction risk. In conclusion, our study shows a meaningful, protective role of the endogenous opioid system in the prevention of epileptic seizures and that disturbances in that balance may facilitate seizure occurrence.
目前，约有 70%的癫痫患者通过药物治疗成功控制了癫痫发作，但仍有约 30%的患者对现有治疗方法存在耐药性。因此，有效治疗癫痫仍然是一个挑战。在我们的研究中，我们利用两种内源性阿片系统活性高低不同的小鼠品系，研究阿片系统的下调或上调与癫痫易感性之间的关系。戊四氮（PTZ）是一种常用于动物模型全面强直阵挛性癫痫发作诱导的化合物。我们的实验表明，在 LA 小鼠中，PTZ 引起的癫痫发作强度更高，潜伏期更短。这一观察结果表明，适当的阿片系统张力对于预防全面强直阵挛性癫痫发作的发生至关重要。此外，阿片受体拮抗剂-纳洛酮（naloxone）和 GABA 受体激动剂-地西泮（DZP）的联合应用可显著减少 DZP 的使用。这对于神经科患者的药物治疗尤为重要，因为苯二氮䓬类药物具有较高的成瘾风险。总之，我们的研究表明，内源性阿片系统在预防癫痫发作中具有重要的保护作用，而这种平衡的紊乱可能会促进癫痫的发生。
