Nascimento C G O, Branco L G S
Departamento de Fisiologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
Braz J Med Biol Res. 2009 Jan;42(1):141-7. doi: 10.1590/s0100-879x2009000100020.
We have shown that the peripheral and spinal cord heme oxygenase (HO)-carbon monoxide (CO)-soluble guanylate cyclase-cGMP pathways play an important role in antinociception in the rat experimental formalin model. Our objective was to determine if there is synergism between peripheral (paw) and spinal HO-CO pathways in nociception. Rats were handled and adapted to the experimental environment for a few days before the formalin test, in which 50 microL of a 1% formalin was injected subcutaneously into the dorsal surface of the right hind paw. The animals were then observed for 1 h and the frequency of flinching behavior was taken to represent the nociceptive response. Thirty minutes before the test, rats were pretreated with intrathecal injections of the HO inhibitor, zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) or heme-lysinate, which is a substrate of the HO pathway. The paw treatments took place 20 min before the test. Low doses of ZnDPBG did not increase nociception, while a low heme-lysinate dose did not change flinching behavior after paw or spinal injections. Combined subactive spinal (50 nmol) and peripheral (40 nmol) low doses of ZnDPBG induced hypernociception (increase of 80% in the first and 25% in the second phase flinching), whereas combined spinal-peripheral heme-lysinate (50 and 30 nmol) led to second phase antinociception (40% reduction in flinching). These findings suggest a synergy between the peripheral and spinal HO-CO pathways. Local activation of the HO system probably regulates the nociception initiation in peripheral tissue and participates in buffering the emerging nociceptive signals at the peripheral and spinal sites of action. In short, an antinociceptive synergy exists between peripheral and spinal HO pathways, which may reduce the doses required and side effects.
我们已经表明，外周和脊髓血红素加氧酶（HO）-一氧化碳（CO）-可溶性鸟苷酸环化酶-cGMP途径在大鼠实验性福尔马林模型的抗伤害感受中起重要作用。我们的目的是确定在伤害感受方面外周（爪）和脊髓HO-CO途径之间是否存在协同作用。在福尔马林试验前，将大鼠处理并使其适应实验环境几天，在该试验中，将50微升1%的福尔马林皮下注射到右后爪的背侧表面。然后观察动物1小时，并将退缩行为的频率作为伤害性反应的指标。在试验前30分钟，大鼠经鞘内注射HO抑制剂、2,4-双乙二醇锌原卟啉（ZnDPBG）或血红素赖氨酸盐（HO途径的一种底物）进行预处理。爪部处理在试验前20分钟进行。低剂量的ZnDPBG不会增加伤害感受，而低剂量的血红素赖氨酸盐在爪部或脊髓注射后不会改变退缩行为。联合使用亚有效剂量的脊髓（50纳摩尔）和外周（40纳摩尔）低剂量ZnDPBG会诱导痛觉过敏（第一阶段退缩增加80%，第二阶段退缩增加25%），而联合使用脊髓-外周血红素赖氨酸盐（50和30纳摩尔）则导致第二阶段抗伤害感受（退缩减少40%）。这些发现表明外周和脊髓HO-CO途径之间存在协同作用。HO系统的局部激活可能调节外周组织中伤害感受的起始，并参与在外周和脊髓作用部位缓冲新出现的伤害性信号。简而言之，外周和脊髓HO途径之间存在抗伤害感受协同作用，这可能会减少所需剂量和副作用。
