Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
Neurosci Lett. 2022 Jan 10;767:136310. doi: 10.1016/j.neulet.2021.136310. Epub 2021 Oct 29.
Neuropathic pain remains one of the most intractable types of pain; although calcium channel αδ ligands, such as pregabalin and gabapentin, are classified as first-line drugs, they have only modest efficacy. Heme oxygenase-1 (HO-1) signaling attenuates glial activation during neuropathic pain. Thus, this study aimed to investigate the effects of the blood-brain barrier (BBB)-permeable HO-1 inhibitor, tin protoporphyrin IX (SnPP), or the BBB-impermeable HO-1 inhibitor, zinc (II) protoporphyrin IX (ZnPP), on the analgesic efficacy of pregabalin and gabapentin. Additionally, we examined the effects of co-administration of SnPP with pregabalin or gabapentin on the expression of glial markers or other genes.
Neuropathic pain was induced by spared nerve injury (SNI) of the sciatic nerve. The mechanical threshold was tested using the von Frey filaments. The expression of spinal glial markers or other genes was examined using reverse transcription polymerase chain reaction.
Systemic HO-1 inhibition reversed the mechanical antiallodynic effects of pregabalin and gabapentin, although peripheral HO-1 inhibition did not alter the mechanical antiallodynic effects of either pregabalin or gabapentin. Intrathecal injection of SnPP or ZnPP abolished the mechanical antiallodynic effects of pregabalin and gabapentin. Pregabalin and gabapentin increased HO-1, arginase-1, and endogenous opioid precursor preproenkephalin gene expression and decreased the expression of glial markers, interleukin-1β, and inducible nitric oxide synthase.
This study suggests that spinal HO-1 plays a crucial role in the analgesic effects of calcium channel αδ ligands through the attenuation of glial activation and endogenous opioid release.
神经病理性疼痛仍然是最棘手的疼痛类型之一；尽管钙通道 αδ 配体（如普瑞巴林和加巴喷丁）被归类为一线药物，但它们的疗效仅为中等。血红素加氧酶-1（HO-1）信号在神经病理性疼痛中减弱胶质细胞的激活。因此，本研究旨在探讨血脑屏障（BBB）通透性 HO-1 抑制剂锡原卟啉 IX（SnPP）或 BBB 非通透性 HO-1 抑制剂锌原卟啉 IX（ZnPP）对普瑞巴林和加巴喷丁镇痛效果的影响。此外，我们还研究了 SnPP 与普瑞巴林或加巴喷丁联合给药对胶质标志物或其他基因表达的影响。
通过坐骨神经 spared 神经损伤（SNI）诱导神经病理性疼痛。使用 von Frey 纤维测试机械阈值。使用逆转录聚合酶链反应检查脊髓胶质标志物或其他基因的表达。
系统 HO-1 抑制逆转了普瑞巴林和加巴喷丁的机械抗痛觉过敏作用，尽管外周 HO-1 抑制并未改变普瑞巴林或加巴喷丁的机械抗痛觉过敏作用。鞘内注射 SnPP 或 ZnPP 消除了普瑞巴林和加巴喷丁的机械抗痛觉过敏作用。普瑞巴林和加巴喷丁增加了 HO-1、精氨酸酶-1 和内源性阿片前体 preproenkephalin 基因的表达，并降低了胶质标志物、白细胞介素-1β 和诱导型一氧化氮合酶的表达。
本研究表明，脊髓 HO-1 通过减弱胶质细胞激活和内源性阿片释放，在钙通道 αδ 配体的镇痛作用中发挥关键作用。
