Nishiyama Tomoki, Chiba Shunsuke, Yamada Yoshitsugu
Department of Anesthesiology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
Eur J Pharmacol. 2008 Oct 31;596(1-3):56-61. doi: 10.1016/j.ejphar.2008.07.054. Epub 2008 Jul 31.
Antinociceptive effects of a new water-soluble sedative agent, an isoindolin-1-one derivative, (-)-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-2-phenyl-3,5,6,7-tetrahydrocyclopenta[f]isoindol-1-(2H)-one (JM 1232 (-)) were studied in two different nociceptive models of rats. Sprague-Dawley rats with lumbar intrathecal catheters were tested for their thermal tail withdrawal response and for their paw flinches by formalin injection after intrathecal administration of various doses of JM 1232 (-). The effects of intraperitoneal administration were also investigated. In addition, behavioral side effects were examined. When antinociceptive effects were observed, the effects of pretreatment with flumazenil or naloxone for the maximum effective dose were evaluated. Eight rats were used in each dose of each group. Intrathecal JM 1232 (-) increased the tail flick latency and decreased the number of flinches in both phases 1 and 2 of the formalin test. These changes were antagonized by intrathecal flumazenil but not by naloxone. Intraperitoneal JM 1232 (-) had no effects on the tail flick latency, but decreased the number of flinches in both phases 1 and 2 of the formalin test. The latter was antagonized by intraperitoneal flumazenil and naloxone with bigger effects of flumazenil. Intraperitoneal JM 1232 (-) 3000 microg induced reversible motor disturbance. In conclusion, intrathecal JM 1232 (-) exerts antinociceptive effects on acute thermal and inflammatory stimuli through benzodiazepine-GABA(A) receptors in the spinal cord. Intraperitoneal JM 1232 (-) was antinociceptive only against inflammatory stimulus and this is mediated mainly by benzodiazepine-GABA(A) receptors, but partially by micro-opioid receptors in the brain.
一种新型水溶性镇静剂——异吲哚啉 - 1 - 酮衍生物（-）-3 - [2 -（4 - 甲基 - 1 - 哌嗪基）-2 - 氧代乙基]-2 - 苯基 - 3,5,6,7 - 四氢环戊[f]异吲哚 - 1 -（2H）- 酮（JM 1232（-））的抗伤害感受作用在两种不同的大鼠伤害感受模型中进行了研究。对带有腰段鞘内导管的Sprague - Dawley大鼠在鞘内注射不同剂量的JM 1232（-）后，测试其热尾撤离反应以及通过福尔马林注射引起的爪退缩反应。还研究了腹腔注射的效果。此外，检查了行为副作用。当观察到抗伤害感受作用时，评估用氟马西尼或纳洛酮预处理对最大有效剂量的影响。每组每个剂量使用8只大鼠。鞘内注射JM 1232（-）增加了福尔马林试验第1和第2阶段的甩尾潜伏期并减少了退缩次数。这些变化被鞘内注射氟马西尼拮抗，但不被纳洛酮拮抗。腹腔注射JM 1232（-）对甩尾潜伏期无影响，但减少了福尔马林试验第1和第2阶段的退缩次数。后者被腹腔注射氟马西尼和纳洛酮拮抗，氟马西尼的作用更大。腹腔注射3000微克JM 1232（-）引起可逆性运动障碍。总之，鞘内注射JM 1232（-）通过脊髓中的苯二氮䓬 - GABA（A）受体对急性热刺激和炎症刺激发挥抗伤害感受作用。腹腔注射JM 1232（-）仅对炎症刺激有抗伤害感受作用，这主要由苯二氮䓬 - GABA（A）受体介导，但部分由脑中的微阿片受体介导。
