Hama A T, Siegan J B, Herzberg U, Sagen J
Department of Anatomy and Cell Biology, University of Illinois at Chicago, 60612, USA.
Pharmacol Biochem Behav. 1999 Jan;62(1):67-74. doi: 10.1016/s0091-3057(98)00132-4.
N-methyl-D-aspartate (NMDA) receptor activation is thought to initiate a cellular cascade of events in the spinal cord that leads to neuronal hyperactivation and exaggerated persistent pain behaviors. Previous studies have demonstrated that implantation of adrenal medullary tissue into the spinal subarachnoid space reduces abnormal pain behaviors such as hyperalgesia and allodynia, possibly by intervening in the NMDA hyperexcitability cascade. Histogranin is a 15-amino acid peptide possessing NMDA receptor antagonist activity that has been isolated from adrenal medullary tissue. The present study examined the ability of stable analog [Ser1]histogranin to reduce abnormal pain-related behaviors induced in rats by direct activation of spinal NMDA receptors. The intrathecal injection of NMDA (5.0, 10.0, 20.0 nmol) produced significant thermal and mechanical hyperalgesia and tactile allodynia in a dose-related fashion. [Ser1]histogranin injected intrathecally prior to NMDA injections dose dependently attenuated or completely blocked hyperalgesia and allodynia. In addition, [Ser1]histogranin administration following NMDA-induction of abnormal pain behaviors reversed these effects. These results demonstrate that a naturally derived adrenal medullary neuropeptide can prevent and reverse NMDA-mediated spinal hyperexcitability. The distinct profile and robust activity of [Ser1]histogranin suggest novel alternative approaches in the management of pain and other CNS disorders involving abnormal excitatory neurotransmission.
N-甲基-D-天冬氨酸（NMDA）受体激活被认为会引发脊髓中的一系列细胞事件，导致神经元过度激活和夸张的持续性疼痛行为。先前的研究表明，将肾上腺髓质组织植入脊髓蛛网膜下腔可减少异常疼痛行为，如痛觉过敏和异常性疼痛，可能是通过干预NMDA过度兴奋级联反应来实现的。组织颗粒蛋白是一种从肾上腺髓质组织中分离出的具有NMDA受体拮抗活性的15个氨基酸的肽。本研究检测了稳定类似物[Ser1]组织颗粒蛋白减少因直接激活脊髓NMDA受体而在大鼠中诱导的异常疼痛相关行为的能力。鞘内注射NMDA（5.0、10.0、20.0纳摩尔）以剂量相关的方式产生了显著的热痛觉过敏、机械性痛觉过敏和触觉异常性疼痛。在注射NMDA之前鞘内注射[Ser1]组织颗粒蛋白可剂量依赖性地减轻或完全阻断痛觉过敏和异常性疼痛。此外，在NMDA诱导异常疼痛行为后给予[Ser1]组织颗粒蛋白可逆转这些效应。这些结果表明，一种天然来源的肾上腺髓质神经肽可以预防和逆转NMDA介导的脊髓过度兴奋。[Ser1]组织颗粒蛋白独特的特性和强大的活性提示在疼痛管理以及其他涉及异常兴奋性神经传递的中枢神经系统疾病方面有新的替代方法。
