Bonnefont Jérôme, Alloui Abdelkrim, Chapuy Eric, Clottes Eric, Eschalier Alain
E9904, Pharmacologie Fondamentale et Clinique de la Douleur, Faculté de médecine, Clermont-Ferrand, France.
Anesthesiology. 2003 Oct;99(4):976-81. doi: 10.1097/00000542-200310000-00034.
The mechanism of action of paracetamol (acetaminophen) remains elusive because it is still under discussion as to whether it acts locally and/or centrally. The primary aim of this study was to clarify its site(s) of action (central and/or local) using the rat formalin test.
Spontaneous biting and licking of the injected paw following intraplantar injection of formalin 2.5% was monitored during the two phases of nociceptive behavior (0-5 and 20-40 min after injection), and the authors examined the antinociceptive activity of paracetamol following oral, intravenous, intraplantar, and intrathecal administrations as well as the reversion of this effect by an intrathecal injection of WAY 100,635, a selective 5-HT1A receptor antagonist.
The oral administration of paracetamol (300, 400 mg/kg) reduced nociceptive behavior in both phases (400 mg/kg: 36.9 +/- 4.6% and 61.5 +/- 5.2% of inhibition in phases I and II, respectively, P <0.05), whereas lower doses reduced primarily the score of the second phase of the test. Only high doses of 10 to 20 mg/kg intraplantarly administered paracetamol, which were ineffective when administered subcutaneously, produced a significant but limited reduction in the early phase of the test and had no effect on the second phase or any antiinflammatory activity. Thus, this local effect did not seem to participate in the antinociceptive action of 400 mg/kg orally given paracetamol, which was totally blocked in both phases by an intrathecal injection of 40 microg WAY 100,635 per rat. Such an inhibition was not observed when paracetamol (200 microg per rat) was intrathecally coinjected with WAY 100,635, whereas the antinociceptive action of 5-HT (50 microg per rat, intrathecally) during both phases of pain was inhibited by WAY 100,635 (intrathecally).
Orally administered paracetamol does not seem to exert any relevant local action in the formalin model of tonic pain in rats, but it might activate the serotonergic bulbospinal pathways via a supraspinal site of action that remains to be elucidated.
对乙酰氨基酚（扑热息痛）的作用机制仍不清楚，因为其作用是局部性的还是/及中枢性的仍在讨论中。本研究的主要目的是通过大鼠福尔马林试验阐明其作用部位（中枢和/或局部）。
在伤害性反应行为的两个阶段（注射后0 - 5分钟和20 - 40分钟）监测足底注射2.5%福尔马林后注射爪的自发咬舔行为，作者研究了口服、静脉注射、足底注射和鞘内注射对乙酰氨基酚后的抗伤害感受活性，以及鞘内注射选择性5-HT1A受体拮抗剂WAY 100,635对这种作用的逆转情况。
口服对乙酰氨基酚（300、400毫克/千克）在两个阶段均降低了伤害性反应行为（400毫克/千克：在第一阶段和第二阶段的抑制率分别为36.9±4.6%和61.5±5.2%，P<0.05），而较低剂量主要降低了试验第二阶段的评分。只有足底注射10至20毫克/千克的高剂量对乙酰氨基酚（皮下注射无效）在试验早期产生了显著但有限的降低，且对第二阶段或任何抗炎活性均无影响。因此，这种局部作用似乎未参与口服400毫克/千克对乙酰氨基酚的抗伤害感受作用，鞘内注射每只大鼠40微克WAY 100,635可在两个阶段完全阻断该作用。当对乙酰氨基酚（每只大鼠200微克）与WAY 100,635鞘内联合注射时未观察到这种抑制作用，而WAY 100,635（鞘内注射）可抑制疼痛两个阶段中5-HT（每只大鼠50微克，鞘内注射）的抗伤害感受作用。
口服对乙酰氨基酚在大鼠紧张性疼痛的福尔马林模型中似乎未发挥任何相关的局部作用，但它可能通过一个尚待阐明的脊髓上作用部位激活血清素能延髓脊髓通路。
