Department of Anatomy and Cell Biology, Oklahoma State University Center for Health Sciences, Tulsa, OK, USA.
Neurosci Lett. 2010 Mar 26;472(3):157-60. doi: 10.1016/j.neulet.2010.01.066. Epub 2010 Feb 2.
In inflamed tissue, the levels of the excitatory amino acid glutamate are increased. Glutamate sensitizes peripheral axons of primary afferent neurons during inflammation leading to decreased firing threshold and hyperexcitability. One proposed source of glutamate is the primary afferent. Antagonizing glutamate receptors on peripheral axons of primary afferents during inflammation provides analgesia in animals and humans. The enzyme glutaminase is used by primary sensory neurons to convert glutamine to glutamate, and peripheral inhibition of glutaminase with 6-diazo-5-oxo-l-norleucine (DON) provides long-lasting analgesia during inflammation. In this study, we measured the effects of glutaminase inhibition on carrageenan-induced spinal Fos expression. Rats were given intraplantar injections of carrageenan and treated locally with either vehicle or DON. After 3h of inflammation, hind paw swelling and spinal expression of Fos were examined. CellProfiler was used to automate Fos nuclei counting in five laminar groupings in the spinal cord (I-II, III-IV, V-VI, VII-IX, X). Carrageenan increased hind paw thickness by approximately 70% and spinal Fos expression in superficial (I-II) and deep (V-VI) laminae by 10-fold and 5-fold, respectively. Treatment with DON reduced hind paw swelling by approximately 13% and suppressed Fos expression in the laminae I-II by approximately 54%, but not the deep laminae. Our results further support the notion of glutamate as a peripheral inflammatory mediator and indicate that glutaminase should be considered as a novel therapeutic target for treatment of inflammatory pain.
在炎症组织中，兴奋性氨基酸谷氨酸的水平增加。在炎症过程中，谷氨酸使初级传入神经元的外周轴突敏化，导致放电阈值降低和过度兴奋。谷氨酸的一个潜在来源是初级传入神经。在炎症过程中，拮抗初级传入神经外周轴突上的谷氨酸受体可在动物和人类中提供镇痛作用。谷氨酰胺酶被初级感觉神经元用于将谷氨酰胺转化为谷氨酸，而用 6-二氮-5-氧-L-正亮氨酸（DON）抑制外周的谷氨酰胺酶可在炎症过程中提供持久的镇痛作用。在这项研究中，我们测量了谷氨酰胺酶抑制对卡拉胶诱导的脊髓 Fos 表达的影响。大鼠接受足底注射卡拉胶，并局部给予载体或 DON。在炎症 3 小时后，检查后爪肿胀和脊髓 Fos 表达。使用 CellProfiler 自动计算脊髓五个层（I-II、III-IV、V-VI、VII-IX、X）中 Fos 核的计数。卡拉胶使后爪厚度增加了约 70%，并使浅层（I-II）和深层（V-VI）脊髓 Fos 表达分别增加了 10 倍和 5 倍。DON 治疗使后爪肿胀减少了约 13%，并使浅层 I-II 层的 Fos 表达减少了约 54%，但对深层脊髓无影响。我们的结果进一步支持了谷氨酸作为外周炎症介质的观点，并表明谷氨酰胺酶应被视为治疗炎症性疼痛的新治疗靶点。
