Department of Pharmaceutical and Biomedical Sciences, 15506The University of Georgia College of Pharmacy, Athens, GA, USA.
Department of Biomedical Sciences, 12241Mercer University School of Medicine, Macon, GA, USA.
Mol Pain. 2022 Apr;18:17448069221107781. doi: 10.1177/17448069221107781.
Spinal neuroinflammation plays a critical role in the genesis of neuropathic pain. Accumulating data suggest that abscisic acid (ABA), a phytohormone, regulates inflammatory processes in mammals. In this study, we found that reduction of the LANCL2 receptor protein but not the agonist ABA in the spinal cord is associated with the genesis of neuropathic pain. Systemic or intrathecal administration of ABA ameliorates the development and pre-existence of mechanical allodynia and heat hyperalgesia in animals with partial sciatic nerve ligation (pSNL). LANCL2 is expressed only in microglia in the spinal dorsal horn. Pre-emptive treatment with ABA attenuates activation of microglia and astrocytes, ERK activity, and TNFα protein abundance in the dorsal horn in rats with pSNL. These are accompanied by restoration of spinal LANCL2 protein abundance. Spinal knockdown of LANCL2 gene with siRNA recapitulates the behavioral and spinal molecular changes induced by pSNL. Activation of spinal toll-like receptor 4 (TLR4) with lipopolysaccharide leads to activation of microglia, and over production of TNFα, which are concurrently accompanied by suppression of protein levels of LANCL2 and peroxisome proliferator activated-receptor γ. These changes are ameliorated when ABA is added with LPS. The anti-inflammatory effects induced by ABA do not requires G protein activity. Our study reveals that the ABA/LANCL2 system is a powerful endogenous system regulating spinal neuroinflammation and nociceptive processing, suggesting the potential utility of ABA as the management of neuropathic pain.
脊髓神经炎症在神经病理性疼痛的发生中起着关键作用。越来越多的证据表明，脱落酸（ABA）作为一种植物激素，调节哺乳动物的炎症过程。在本研究中，我们发现脊髓中 LANCL2 受体蛋白的减少而不是激动剂 ABA 与神经病理性疼痛的发生有关。全身或鞘内给予 ABA 可改善部分坐骨神经结扎（pSNL）动物机械性痛觉过敏和热痛觉过敏的发展和预先存在。LANCL2 仅在脊髓背角的小胶质细胞中表达。预先用 ABA 处理可减轻 pSNL 大鼠背角小胶质细胞和星形胶质细胞的激活、ERK 活性和 TNFα 蛋白丰度。这些变化伴随着脊髓 LANCL2 蛋白丰度的恢复。用 siRNA 对脊髓 LANCL2 基因进行敲低可重现 pSNL 诱导的行为和脊髓分子变化。用脂多糖激活脊髓 toll 样受体 4（TLR4）可导致小胶质细胞的激活和 TNFα 的过度产生，同时伴随着 LANCL2 和过氧化物酶体增殖物激活受体 γ 的蛋白水平抑制。当 LPS 中加入 ABA 时，这些变化得到改善。ABA 诱导的抗炎作用不依赖于 G 蛋白活性。我们的研究揭示了 ABA/LANCL2 系统是调节脊髓神经炎症和伤害性处理的强大内源性系统，这表明 ABA 作为神经病理性疼痛管理的潜在用途。
