Dirig D M, Isakson P C, Yaksh T L
Department of Pharmacology, University of California, San Diego, California, USA.
J Pharmacol Exp Ther. 1998 Jun;285(3):1031-8.
Intrathecal administration of nonsteroidal anti-inflammatory drugs in the rat blocks the thermal hyperalgesia induced by tissue injury, which suggests a role for spinal cyclooxygenase (COX) products in this facilitated state. Two isozymes of the COX enzyme have been reported, COX-1 and COX-2, but the agents thus far examined are not isozyme selective. We examined the effects of intrathecally (i.t.) or systemically (i.p.) administered S(+)-ibuprofen (a nonselective COX inhibitor) or 1-[(4-methysulfonyl)phenyl]-3-tri-fluoromethyl-5-(4-fluorophenyl) pyrazole (SC58125; a COX-2 selective inhibitor) on carrageenan-induced thermal hyperalgesia (reduced hindpaw-withdrawal latency). The following observations were made: 1) Thermal hyperalgesia otherwise observed during the first 170 min was blocked in a dose-dependent manner by S(+)-ibuprofen or SC58125 administered i.t. or i.p. before carrageenan treatment. 2) Intraperitoneal, but not i.t., administration of either inhibitor after the establishment of hyperalgesia (170 min after carrageenan injection) reversed thermal hyperalgesia in a dose-dependent manner. Thus, the initial component of thermal hyperalgesia after tissue injury was blocked by systemic or spinal administration of both COX inhibitors, whereas established hyperalgesia was reversed only by systemic inhibitors. This study demonstrates that at least spinal COX-2, if not both COX-1 and COX-2, are necessary for the initiation of thermal hyperalgesia, whereas nonspinal sources of prostanoids (synthesized by COX-2 and perhaps also COX-1) are important for the maintenance of thermal hyperalgesia associated with tissue injury and inflammation.
在大鼠中鞘内注射非甾体抗炎药可阻断由组织损伤诱导的热痛觉过敏，这表明脊髓环氧化酶（COX）产物在这种易化状态中起作用。已报道COX酶有两种同工酶，即COX-1和COX-2，但迄今为止所研究的药物并非同工酶选择性的。我们研究了鞘内（i.t.）或全身（i.p.）给予S（+）-布洛芬（一种非选择性COX抑制剂）或1-[(4-甲磺酰基)phenyl]-3-三氟甲基-5-(4-氟苯基)吡唑（SC58125；一种COX-2选择性抑制剂）对角叉菜胶诱导的热痛觉过敏（后爪缩足潜伏期缩短）的影响。得到了以下观察结果：1）在角叉菜胶处理前鞘内或腹腔注射S（+）-布洛芬或SC58125，以剂量依赖性方式阻断了原本在最初170分钟内观察到的热痛觉过敏。2）在痛觉过敏建立后（角叉菜胶注射后170分钟）腹腔注射任何一种抑制剂均可剂量依赖性地逆转热痛觉过敏，但鞘内注射则不能。因此，组织损伤后热痛觉过敏的初始成分可通过全身或脊髓给予两种COX抑制剂而被阻断，而已经形成的痛觉过敏仅可被全身抑制剂逆转。本研究表明，至少脊髓COX-2（如果不是COX-1和COX-2两者的话）是热痛觉过敏起始所必需的，而前列腺素的非脊髓来源（由COX-2或许还有COX-1合成）对于与组织损伤和炎症相关的热痛觉过敏的维持很重要。
