Effects of kappa-opioid agonist U-50488 and p38 MAPK inhibitor SB203580 on the spike activity of pyramidal neurons in the basolateral amygdala

Q3 Pharmacology, Toxicology and Pharmaceutics
K. Kalitin, A. Spasov, O. Mukha
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Abstract

Introduction: Kappa-opioid receptor (KOR) signaling in the basolateral amygdala (BLA) underlies KOR agonist-induced aversion. In this study, we aimed to understand the individual and combined effects of KOR agonist U-50488 and p38 MAPK inhibitor SB203580 on the spiking activity of pyramidal neurons in the BLA to shed light on the complex interplay between KORs, the p38 MAPK, and neuronal excitability. Materials and Methods: Electrophysiological experiments were performed using the patch-clamp technique in the whole-cell configuration. Rat brain slices containing the amygdala were prepared, and pyramidal neurons within the BLA were visually patched and recorded in the current clamp mode. The neurons were identified by their accommodation properties and neural activity signals were amplified and analyzed. Using local perfusion, we obtained three dose-response curves for: (a) U-50488 (0.001–10 μM); (b) U-50488 (0.001–10 μM) in the presence of SB203580 (1 μM); and (c) U-50488 (0.01–10 μM) in the presence of SB203580 (5 μM). Results: After the application of U-50488, pyramidal neurons had a higher action potential firing rate in response to a current injection than control neurons (p<0.001). The dose-dependent curves we obtained indicate that the combination of U-50488 and SB203580 results in non-competitive antagonism. This conclusion is supported by the observed change in the curve’s slope with reduction in the maximum effect of U-50488. Thus, it can be assumed that the increase in spike activity of pyramidal neurons of the amygdala is mediated through the beta-arrestin pathway. When this pathway is blocked, the spike activity reverts to its baseline level. Conclusion: Our study found that the KOR agonist-induced spiking activity of the BLA pyramidal neurons is mediated by the beta-arrestin pathway and can be suppressed by the application of the p38 MAPK inhibitor SB203580.
卡巴阿片激动剂 U-50488 和 p38 MAPK 抑制剂 SB203580 对杏仁核基底外侧锥体神经元尖峰活动的影响
引言杏仁基底外侧(BLA)的卡帕阿片受体(KOR)信号是KOR激动剂诱导厌恶的基础。在本研究中,我们旨在了解 KOR 激动剂 U-50488 和 p38 MAPK 抑制剂 SB203580 对杏仁核锥体神经元尖峰活动的单独和联合影响,以揭示 KOR、p38 MAPK 和神经元兴奋性之间复杂的相互作用:电生理实验采用全细胞结构的膜片钳技术。制备包含杏仁核的大鼠脑片,在电流钳模式下对杏仁核内的锥体神经元进行视觉贴片和记录。根据神经元的容纳特性对其进行识别,并对神经活动信号进行放大和分析。通过局部灌注,我们得到了以下三种药物的剂量反应曲线:(a) U-50488 (0.001-10 μM);(b) U-50488 (0.001-10 μM)与 SB203580 (1 μM);(c) U-50488 (0.01-10 μM)与 SB203580 (5 μM):施用 U-50488 后,锥体神经元对电流注入的动作电位发射率高于对照神经元(p<0.001)。我们获得的剂量依赖性曲线表明,U-50488 和 SB203580 的组合产生了非竞争性拮抗作用。随着 U-50488 最大效应的降低,观察到的曲线斜率变化也支持了这一结论。因此,可以推测杏仁核锥体神经元尖峰活动的增加是通过β-阿司匹林途径介导的。当这条途径被阻断时,尖峰活动会恢复到基线水平:我们的研究发现,KOR 激动剂诱导的杏仁核锥体神经元尖峰活动是由β-阿司匹林通路介导的,并且可以通过应用 p38 MAPK 抑制剂 SB203580 得到抑制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Research Results in Pharmacology
Research Results in Pharmacology Medicine-Pharmacology (medical)
CiteScore
1.50
自引率
0.00%
发文量
32
审稿时长
12 weeks
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