Okajima Kenji, Harada Naoaki
Department of Biodefense Medicine, Nagoya City University Graduate School of Medical Sciences, Japan.
Curr Med Chem. 2006;13(19):2241-51. doi: 10.2174/092986706777935131.
Capsaicin-sensitive sensory neurons are nociceptive neurons that release calcitonin gene-related peptide (CGRP) on activation. Since CGRP has potent vasodilatory activity, it has long been considered to be involved in aggravation of inflammation such as tissue hyperemia and edema. However, since ablation of the sensory fibers can result in a marked increase in the severity of inflammation and reperfusion-induced tissue inflammatory responses are enhanced in congenital CGRP-knockout mice, the sensory neurons have been shown to play a role in the maintenance of tissue integrity by regulating local inflammatory responses. We demonstrated in rodents that stimulation of sensory neurons reduces hypertension, stress-induced gastric mucosal injury, reperfusion-induced liver injury, and endotoxin-induced shock responses by attenuating inflammatory responses such as increases in both tissue levels of tumor necrosis factor (TNF) and tissue accumulation of neutrophils. Attenuation of inflammatory responses by sensory neuron activation can be explained mainly by CGRP-induced increase in the endothelial production of prostacyclin (PGI(2)). Since inflammatory responses are critically involved in the development of a wide variety of diseases, pharmacological stimulation of sensory neurons might contribute to treatment of various pathologic conditions. In this review, the authors describe molecular mechanism(s) by which sensory neuron activation inhibits TNF production, thereby attenuating inflammatory responses. Furthermore, the authors discuss some clinically useful therapeutic agents that are capable of activating sensory neurons and raise the possibility that pharmacological stimulation of sensory neurons is the new paradigm for future therapeutic strategies.
辣椒素敏感的感觉神经元是伤害性神经元，激活时会释放降钙素基因相关肽（CGRP）。由于CGRP具有强大的血管舒张活性，长期以来人们一直认为它参与了诸如组织充血和水肿等炎症的加重过程。然而，由于感觉纤维的切除会导致炎症严重程度显著增加，并且在先天性CGRP基因敲除小鼠中再灌注诱导的组织炎症反应增强，已表明感觉神经元通过调节局部炎症反应在维持组织完整性中发挥作用。我们在啮齿动物中证明，刺激感觉神经元可通过减弱炎症反应（如肿瘤坏死因子（TNF）组织水平的升高和中性粒细胞的组织积聚）来降低高血压、应激诱导的胃黏膜损伤、再灌注诱导的肝损伤以及内毒素诱导的休克反应。感觉神经元激活引起的炎症反应减弱主要可通过CGRP诱导内皮细胞前列环素（PGI₂）生成增加来解释。由于炎症反应在多种疾病的发展中起关键作用，感觉神经元的药理学刺激可能有助于治疗各种病理状况。在这篇综述中，作者描述了感觉神经元激活抑制TNF产生从而减弱炎症反应的分子机制。此外，作者讨论了一些能够激活感觉神经元的临床有用治疗药物，并提出感觉神经元的药理学刺激是未来治疗策略新范式的可能性。
