Tappe Anke, Klugmann Matthias, Luo Ceng, Hirlinger David, Agarwal Nitin, Benrath Justus, Ehrengruber Markus U, During Matthew J, Kuner Rohini
Pharmacology Institute, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
Nat Med. 2006 Jun;12(6):677-81. doi: 10.1038/nm1406. Epub 2006 May 21.
Glutamatergic signaling and intracellular calcium mobilization in the spinal cord are crucial for the development of nociceptive plasticity, which is associated with chronic pathological pain. Long-form Homer proteins anchor glutamatergic receptors to sources of calcium influx and release at synapses, which is antagonized by the short, activity-dependent splice variant Homer1a. We show here that Homer1a operates in a negative feedback loop to regulate the excitability of the pain pathway in an activity-dependent manner. Homer1a is rapidly and selectively upregulated in spinal cord neurons after peripheral inflammation in an NMDA receptor-dependent manner. Homer1a strongly attenuates calcium mobilization as well as MAP kinase activation induced by glutamate receptors and reduces synaptic contacts on spinal cord neurons that process pain inputs. Preventing activity-induced upregulation of Homer1a using shRNAs in mice in vivo exacerbates inflammatory pain. Thus, activity-dependent uncoupling of glutamate receptors from intracellular signaling mediators is a novel, endogenous physiological mechanism for counteracting sensitization at the first, crucial synapse in the pain pathway. Furthermore, we observed that targeted gene transfer of Homer1a to specific spinal segments in vivo reduces inflammatory hyperalgesia. Thus, Homer1 function is crucially involved in pain plasticity and constitutes a promising therapeutic target for the treatment of chronic inflammatory pain.
脊髓中的谷氨酸能信号传导和细胞内钙动员对于伤害性可塑性的发展至关重要，而伤害性可塑性与慢性病理性疼痛相关。长链荷马蛋白将谷氨酸能受体锚定到突触处的钙流入源和释放源，而短的、依赖活性的剪接变体荷马1a则对其产生拮抗作用。我们在此表明，荷马1a以依赖活性的方式在负反馈回路中发挥作用，以调节疼痛通路的兴奋性。在外周炎症后，荷马1a在脊髓神经元中以依赖N-甲基-D-天冬氨酸受体的方式迅速且选择性地上调。荷马1a强烈减弱谷氨酸受体诱导的钙动员以及丝裂原活化蛋白激酶激活，并减少处理疼痛输入的脊髓神经元上的突触接触。在小鼠体内使用短发夹RNA阻止活性诱导的荷马1a上调会加剧炎性疼痛。因此，谷氨酸受体与细胞内信号介质的活性依赖性解偶联是一种新的内源性生理机制，可在疼痛通路的第一个关键突触处对抗敏化。此外，我们观察到在体内将荷马1a靶向基因转移到特定脊髓节段可减轻炎性痛觉过敏。因此，荷马蛋白功能在疼痛可塑性中起着关键作用，并构成治疗慢性炎性疼痛的一个有前景的治疗靶点。
