Aumeerally N, Allen G, Sawynok J
Department of Pharmacology and Anatomy, Dalhousie University, Halifax, Nova Scotia, Canada B3H 1X5.
Neuroscience. 2004;127(1):1-11. doi: 10.1016/j.neuroscience.2004.04.012.
Glutamate (which facilitates peripheral nociception) releases adenosine (which inhibits peripheral nociception via adenosine A(1) receptors) when injected locally into the rat hindpaw. The present study determined whether this locally released adenosine could modulate spontaneous pain behaviors produced by a local injection of 1.5% formalin, by determining the effect of 8-cyclopentyl-theophylline (CPT; selective adenosine A(1) receptor antagonist) on flinching produced by formalin/glutamate combinations. Experiments were performed following a prior conditioning injection of 2.5% formalin into the contralateral hindpaw 3-4 days earlier. CPT augmented flinching behaviors produced by 1.5% formalin/1 micromol glutamate, but had no effect on behaviors produced by formalin or glutamate alone. CPT also augmented flinches generated by formalin/alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and formalin/kainic acid, but not by formalin/N-methyl-D-aspartate (NMDA) combinations. The conditioning leads to a clearer expression of the peripheral inhibitory effect of adenosine (inhibitory effect of an inhibitor of adenosine kinase on flinching also was observed), rather than an increased release of adenosine (no enhanced release observed by microdialysis). Microglia appear to be involved in the conditioning, as microglia are activated in the dorsal spinal cord 3 days following injection of 2.5% formalin, and augmentation of formalin/glutamate-induced flinching by CPT is inhibited by the glial metabolic inhibitor fluorocitrate. The augmentation of flinching by CPT is also eliminated following a spinal pretreatment with MK-801 (NMDA receptor antagonist), cyclohexyladenosine (adenosine A(1) receptor agonist), N(G)-nitro-L-arginine methyl ester HCl (nitric oxide synthetase inhibitor), and chelerythrine (protein kinase C inhibitor). The conditioning pretreatment with 2.5% formalin does not lead to a generalized chemical or thermal hypersensitivity in the contralateral hindpaw. This study demonstrates that prior exposure to 2.5% formalin in the contralateral hindpaw reveals an inhibitory effect of adenosine on peripheral nociception in the presence of glutamate; this conditioning involves microglia and other mechanisms involved in central sensitization.
谷氨酸（可促进外周伤害感受）局部注射到大鼠后爪时会释放腺苷（通过腺苷A(1)受体抑制外周伤害感受）。本研究通过测定8-环戊基茶碱（CPT；选择性腺苷A(1)受体拮抗剂）对福尔马林/谷氨酸组合引起的退缩反应的影响，来确定这种局部释放的腺苷是否能调节局部注射1.5%福尔马林所产生的自发疼痛行为。实验在3 - 4天前预先对侧后爪注射2.5%福尔马林进行预处理后进行。CPT增强了1.5%福尔马林/1微摩尔谷氨酸引起的退缩行为，但对单独福尔马林或谷氨酸引起的行为没有影响。CPT还增强了福尔马林/α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）和福尔马林/ kainic酸引起的退缩反应，但对福尔马林/N-甲基-D-天冬氨酸（NMDA）组合引起的反应没有增强作用。这种预处理导致腺苷外周抑制作用的更清晰表达（也观察到腺苷激酶抑制剂对退缩反应的抑制作用），而不是腺苷释放增加（微透析未观察到释放增强）。小胶质细胞似乎参与了这种预处理，因为在注射2.5%福尔马林3天后，背侧脊髓中的小胶质细胞被激活，并且CPT对福尔马林/谷氨酸诱导的退缩反应的增强作用被胶质细胞代谢抑制剂氟柠檬酸所抑制。在用MK-801（NMDA受体拮抗剂）、环己基腺苷（腺苷A(1)受体激动剂）、N(G)-硝基-L-精氨酸甲酯盐酸盐（一氧化氮合酶抑制剂）和白屈菜红碱（蛋白激酶C抑制剂）进行脊髓预处理后，CPT对退缩反应的增强作用也被消除。用2.5%福尔马林进行预处理不会导致对侧后爪出现全身性化学或热超敏反应。本研究表明，预先在对侧后爪暴露于2.5%福尔马林可揭示在谷氨酸存在下腺苷对外周伤害感受的抑制作用；这种预处理涉及小胶质细胞和其他参与中枢敏化的机制。
