Chung Ki-Myung, Choi Seong-Soo, Han Ki-Jung, Han Eun-Jung, Lee Han-Kyu, Suh Hong-Won
Department of Physiology and Neuroscience, College of Dentistry and Research Institute of Oral Science, Kangnung National University, Kangnung, South Korea.
Pharmacology. 2003 Oct;69(2):93-101. doi: 10.1159/000072362.
Several studies have demonstrated that the nonselective opioid receptor antagonist naloxone produces a paradoxical antinociception in the formalin test. The opioid system is related to the serotonergic system for producing antinociception at the spinal level. Here we also asked whether systemic (i.p.) and intrathecal (i.t.) administrations of a nonselective serotonergic antagonist, methysergide, might produce paradoxical antinociception similar to naloxone in the mouse formalin test. A diluted formalin solution was injected into the mouse plantar region of the hind paw and the duration of licking responses was measured at periods of 0-5 min (1st phase) and 20-40 min (2nd phase) after formalin injection. Methysergide administered i.p. and i.t. showed an attenuated licking duration only in the 2nd phase. The effect observed in the 2nd phase was reversed in the 5,7-dihydroxytriptamine, but not N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine pretreated group of mice, suggesting that descending serotonergic, but not noradrenergic, systems are involved in the methysergide antinociception. To further investigate the mechanism by which methysergide inhibited the nociceptive behaviors induced by formalin, the antinociceptive effect of methysergide was also tested in substance P (i.t.) and excitatory amino acids (i.t.), such as glutamate, N-methyl-D-aspartic acid, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, and kainic acid, which are major components in the formalin-induced nociceptive transmission in the spinal cord pain models. The duration of nociceptive behaviors shown in these models was significantly shortened by i.p. and i.t. administration of methysergide. These results suggest that methysergide also produces a paradoxical antinociception in various pain models including the formalin test, similar to the results of naloxone.
多项研究表明，非选择性阿片受体拮抗剂纳洛酮在福尔马林试验中会产生反常的抗伤害感受作用。阿片系统与5-羟色胺能系统在脊髓水平产生抗伤害感受作用方面相关。在此，我们还研究了非选择性5-羟色胺能拮抗剂美西麦角经全身（腹腔注射）和鞘内给药是否会在小鼠福尔马林试验中产生与纳洛酮类似的反常抗伤害感受作用。将稀释的福尔马林溶液注射到小鼠后爪的足底区域，并在注射福尔马林后的0-5分钟（第一阶段）和20-40分钟（第二阶段）测量舔舐反应的持续时间。腹腔注射和鞘内注射美西麦角仅在第二阶段显示舔舐持续时间缩短。在5,7-二羟基色胺预处理的小鼠组中，第二阶段观察到的效应被逆转，但在N-(2-氯乙基)-N-乙基-2-溴苄胺预处理的小鼠组中未被逆转，这表明下行5-羟色胺能系统而非去甲肾上腺素能系统参与了美西麦角的抗伤害感受作用。为了进一步研究美西麦角抑制福尔马林诱导的伤害性行为的机制，还在P物质（鞘内注射）和兴奋性氨基酸（鞘内注射）如谷氨酸、N-甲基-D-天冬氨酸、α-氨基-3-羟基-5-甲基异恶唑-4-丙酸和 kainic 酸中测试了美西麦角的抗伤害感受作用，这些物质是脊髓疼痛模型中福尔马林诱导的伤害性传递的主要成分。腹腔注射和鞘内注射美西麦角可显著缩短这些模型中显示的伤害性行为的持续时间。这些结果表明，美西麦角在包括福尔马林试验在内的各种疼痛模型中也会产生反常的抗伤害感受作用，类似于纳洛酮的结果。
