Du J, Zhou S, Carlton S M
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1069, USA.
Neuroscience. 2006 Feb;137(3):999-1013. doi: 10.1016/j.neuroscience.2005.10.008. Epub 2005 Dec 5.
This study investigates contributions of peripheral kainate receptors to acute nociception and persistent inflammatory pain in rat. Immunohistochemical analysis of kainate receptor expression using antibodies recognizing glutamate receptor subunits 5, 6, and 7 demonstrates that 28% of unmyelinated axons in normal digital nerve are positively labeled. Following intraplantar injection of complete Freund's adjuvant, a significant increase in glutamate receptor subunits 5, 6, and 7-labeled axons occurs at 2 days (40%), but not 7 (31%) or 14 days (28%) post-complete Freund's adjuvant. In behavioral studies, we confirm an increased mechanical sensitivity in complete Freund's adjuvant-injected hind paws. Furthermore, activation of kainate receptors following intraplantar injection of 1.0 mM kainate in normal animals results in a mechanical sensitivity similar to that observed in inflamed animals. A 1.0 mM kainate injection into inflamed hind paws further enhances the mechanical sensitivity. Injection of the non-N-methyl-D-aspartate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (0.1 mM) reverses complete Freund's adjuvant-induced mechanical sensitivity through a local effect. In single unit recordings from nociceptors in a glabrous skin-nerve preparation, mechanical sensitization is present in inflamed skin evidenced by a decrease in mechanical threshold and an increase in discharge rate during a suprathreshold, constant force stimulus. Thermal sensitization is also present evidenced by a decrease in heat threshold. There is a dose-dependent increase in kainate-induced nociceptor activity in both normal and inflamed skin but the kainate required to induce activation is reduced in inflamed skin. Although proportions of kainate-activated nociceptors are the same in normal and inflamed skin, the kainate-induced mean discharge rate is significantly enhanced in inflamed skin. Exposure of normal and inflamed nociceptors to 0.3 mM kainate sensitizes fibers to re-application of kainate and heat. This sensitization is blocked in the presence of 6-cyano-7-nitroquinoxaline-2,3-dione or the glutamate receptor subunit 5 selective antagonist 3S,4aR,6S,8aR-6-[4-carboxy-phenyl] methyl-1,2,3,4,4a,5,6,7,8,8a-deca-hydroisoquinoline-3-carboxylic acid. The data indicate that peripheral kainate receptors not only play an important role in normal nociception but also contribute to mechanical sensitivity and heat sensitization accompanying inflammatory pain.
本研究调查了外周海人酸受体对大鼠急性伤害感受和持续性炎症性疼痛的作用。使用识别谷氨酸受体亚基5、6和7的抗体对海人酸受体表达进行免疫组织化学分析表明，正常指神经中28%的无髓轴突呈阳性标记。在足底注射完全弗氏佐剂后，谷氨酸受体亚基5、6和7标记的轴突在完全弗氏佐剂注射后2天（40%）显著增加，但在7天（31%）或14天（28%）时未增加。在行为学研究中，我们证实了注射完全弗氏佐剂的后爪机械敏感性增加。此外，在正常动物足底注射1.0 mM海人酸后激活海人酸受体，会导致与炎症动物中观察到的类似的机械敏感性。向炎症后爪注射1.0 mM海人酸会进一步增强机械敏感性。注射非N-甲基-D-天冬氨酸受体拮抗剂6-氰基-7-硝基喹喔啉-2,3-二酮（0.1 mM）通过局部作用逆转完全弗氏佐剂诱导的机械敏感性。在无毛皮肤-神经制备中对伤害感受器进行单单位记录时，炎症皮肤中存在机械致敏，表现为机械阈值降低和阈上恒力刺激期间放电率增加。热致敏也存在，表现为热阈值降低。在正常皮肤和炎症皮肤中，海人酸诱导的伤害感受器活性均呈剂量依赖性增加，但炎症皮肤中诱导激活所需的海人酸减少。尽管正常皮肤和炎症皮肤中海人酸激活的伤害感受器比例相同，但炎症皮肤中海人酸诱导的平均放电率显著增强。将正常和炎症伤害感受器暴露于0.3 mM海人酸会使纤维对海人酸和热的再次应用敏感。在存在6-氰基-7-硝基喹喔啉-2,3-二酮或谷氨酸受体亚基5选择性拮抗剂3S,4aR,6S,8aR-6-[4-羧基-苯基]甲基-1,2,3,4,4a,5,6,7,8,八氢异喹啉-3-羧酸时，这种致敏被阻断。数据表明，外周海人酸受体不仅在正常伤害感受中起重要作用，而且还参与炎症性疼痛伴随的机械敏感性和热致敏。
