Heme oxygenase-1 in the spinal cord plays crucial roles in the analgesic effects of pregabalin and gabapentin in a spared nerve-injury mouse model
Heme oxygenase-1 in the spinal cord plays crucial roles in the analgesic effects of pregabalin and gabapentin in a spared nerve-injury mouse model
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DOI：
10.1016/j.neulet.2021.136310
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发表时间：
2021-12-16
影响因子：
2.5
通讯作者：
Moriyama, Takahiro
中科院分区：
文献类型：
--
作者：
Godai, Kohei;Moriyama, Takahiro
前言：神经性疼痛仍然是最难治的疼痛类型之一；尽管钙通道α(2)β配体，如普瑞巴林和加巴喷丁，被归类为一线药物，但它们的疗效不大。血红素氧合酶-1(HO-1)信号在神经病理性疼痛中减弱神经胶质细胞的激活。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)或非血脑屏障通透性HO-1抑制剂锌(II)原卟啉IX(ZnPP)对普瑞巴林和加巴喷丁镇痛效果的影响。此外，我们还检测了SnPP与普瑞巴林或加巴喷丁联合应用对神经胶质标记物或其他基因表达的影响。方法：坐骨神经备用神经损伤(SNI)诱导神经病理性疼痛。用冯-弗雷纤维测试了其机械阈值。结果：全身性HO-1抑制逆转了普瑞巴林和加巴喷丁的机械性抗痛觉过敏作用，而外周HO-1抑制不改变普瑞巴林和加巴喷丁的机械性抗痛觉过敏作用。鞘内注射SnPP或ZnPP可阻断普瑞巴林和加巴喷丁的机械性抗痛觉过敏性反应。普瑞巴林和加巴喷丁增加HO-1、精氨酸酶-1和内源性阿片前体前脑啡肽原基因的表达，降低神经胶质细胞标志物、白介素1β和诱导型一氧化氮合酶的表达。结论：脊髓HO-1可能通过抑制神经胶质细胞的激活和内源性阿片类物质的释放，在钙通道α(2)Delta配体的镇痛作用中发挥重要作用。
Introduction: Neuropathic pain remains one of the most intractable types of pain; although calcium channel alpha(2)delta 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.Methods: 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.Results: 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-1 beta, and inducible nitric oxide synthase.Conclusions: This study suggests that spinal HO-1 plays a crucial role in the analgesic effects of calcium channel alpha(2)delta ligands through the attenuation of glial activation and endogenous opioid release.