Inflammation-induced shift in spinal GABA(A) signaling is associated with a tyrosine kinase-dependent increase in GABA(A) current density in nociceptive afferents.
Inflammation-induced shift in spinal GABA(A) signaling is associated with a tyrosine kinase-dependent increase in GABA(A) current density in nociceptive afferents.
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炎症诱导的脊髓 GABA(A) 信号传导转变与伤害性传入神经中 GABA(A) 电流密度的酪氨酸激酶依赖性增加有关。
DOI：
10.1152/jn.00590.2012
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发表时间：
2012
影响因子：
2.5
通讯作者：
Gold,MichaelS
中科院分区：
文献类型：
--
作者：
Zhu,Yi;Dua,Shiv;Gold,MichaelS
为了解释观察到的苯二氮卓类诱导的脊髓镇痛与炎症诱导的 GABAA 受体拮抗剂加巴嗪对伤害性阈值影响的变化有关，本研究旨在确定持续性炎症是否与初级传入神经中高亲和力 GABAA 受体的上调有关。在诱导持续性炎症之前和之后，对支配大鼠后爪无毛皮肤的传入神经的细胞体进行逆行标记、急性分离并进行研究。观察到 GABAA 电流密度随时间的增加，在炎症开始后 72 小时增加两倍以上。这种电流密度的增加包括高亲和力电流和低亲和力电流，并且仅限于 GABA 增加细胞内 Ca2+ 的神经元。在整个神经节中没有检测到 GABAA 受体亚基 mRNA 或蛋白质的增加。相比之下，增加的电流密度通过与酪氨酸激酶抑制剂金雀异黄素预孵育20分钟完全逆转，并且通过Src激酶抑制剂PP2部分逆转。金雀异黄素逆转被动力抑制剂肽 P4 部分阻断。向发炎大鼠脊髓施用金雀异黄酮和蝇蕈醇后伤害感受阈值的变化表明，在存在炎症的情况下观察到的蝇蕈醇的伤害感受作用被金雀异黄素逆转。这些结果表明，炎症后酪氨酸激酶活性相对水平的持续变化不仅提供了动态调节脊髓伤害性信号传导的敏感方法，而且为开发治疗炎性疼痛的新型治疗干预措施提供了可行的目标。
To account for benzodiazepine-induced spinal analgesia observed in association with an inflammation-induced shift in the influence of the GABAAreceptor antagonist gabazine on nociceptive threshold, the present study was designed to determine whether persistent inflammation is associated with the upregulation of high-affinity GABAAreceptors in primary afferents. The cell bodies of afferents innervating the glabrous skin of the rat hind paw were retrogradely labeled, acutely dissociated, and studied before and after the induction of persistent inflammation. A time-dependent increase in GABAAcurrent density was observed that was more than twofold by 72 h after the initiation of inflammation. This increase in current density included both high- and low-affinity currents and was restricted to neurons in which GABA increased intracellular Ca2+. No increases in GABAAreceptor subunit mRNA or protein were detected in whole ganglia. In contrast, the increased current density was completely reversed by 20-min preincubation with the tyrosine kinase inhibitor genistein and partially reversed with the Src kinase inhibitor PP2. Genistein reversal was partially blocked by the dynamin inhibitor peptide P4. Changes in nociceptive threshold following spinal administration of genistein and muscimol to inflamed rats indicated that the pronociceptive actions of muscimol observed in the presence of inflammation were reversed by genistein. These results suggest that persistent changes in relative levels of tyrosine kinase activity following inflammation provide not only a sensitive way to dynamically regulate spinal nociceptive signaling but a viable target for the development of novel therapeutic interventions for the treatment of inflammatory pain.