Oliva Patrizia, Aurilio Caterina, Massimo Francesco, Grella Antonio, Maione Sabatino, Grella Elisa, Scafuro Mariantonietta, Rossi Francesco, Berrino Liberato
Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, Via Costantinopoli, 16, Italy.
Eur J Pharmacol. 2002 Jun 12;445(3):179-85. doi: 10.1016/s0014-2999(02)01647-3.
The aim of this study was to investigate the neurotransmissions involved in the antinociceptive effect of tramadol in the formalin test, which is an animal model of acute and tonic pain. A subcutaneous injection of formalin produces a biphasic nociceptive response: phase 1 (0-10 min-acute pain) and phase 2 (21-60 min-tonic pain). Nociceptive activity is reduced greatly during the 10 min between these two phases. We measured in mice the effects of (+/-)-tramadol, and of (+)- and (-)-tramadol administered before the induction of pain by formalin, in the presence and absence of drugs that act on the opioidergic, serotonergic and noradrenergic systems (naloxone, ketanserin, fluoxetine, maprotiline). With respect to animals treated with formalin alone, (+/-)-tramadol and its enantiomers significantly reduced the duration of nociceptive behaviours (lifting, licking, favouring, shaking, and flinching of the formalin-treated paw) during phase 2. This effect was prevented by the 5-HT(2) receptor antagonist ketanserin, but not by naloxone which, on the contrary, was able to prevent the antinociceptive effect of morphine. Naloxone and ketanserin did not affect the duration of nociceptive behaviour in animals not treated with tramadol. Fluoxetine (a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor), but not maprotiline (a selective norepinephrine reuptake inhibitor), potentiated the antinociceptive effect of (+/-)-tramadol. In conclusion, we demonstrate that the serotonergic pathway is responsible for the antinociceptive effect of tramadol in phase 2 of the formalin test, and that this effect is mediated by 5-HT(2) receptors.
本研究的目的是调查曲马多在福尔马林试验中产生抗伤害感受作用所涉及的神经传递，福尔马林试验是一种急性和持续性疼痛的动物模型。皮下注射福尔马林会产生双相伤害感受反应：第1阶段（0 - 10分钟——急性疼痛）和第2阶段（21 - 60分钟——持续性疼痛）。在这两个阶段之间的10分钟内，伤害感受活动会大幅降低。我们在小鼠中测量了（±）-曲马多以及在福尔马林诱发疼痛之前给予的（+）-和（-）-曲马多的作用，实验中使用了作用于阿片能、5-羟色胺能和去甲肾上腺素能系统的药物（纳洛酮、酮色林、氟西汀、马普替林）。与仅用福尔马林处理的动物相比，（±）-曲马多及其对映体在第2阶段显著缩短了伤害感受行为（福尔马林处理爪的抬起、舔舐、偏好、颤抖和退缩）的持续时间。5-羟色胺（5-HT）2受体拮抗剂酮色林可阻止这种作用，但纳洛酮不能，相反，纳洛酮能够阻止吗啡的抗伤害感受作用。纳洛酮和酮色林对未用曲马多处理的动物的伤害感受行为持续时间没有影响。氟西汀（一种选择性5-羟色胺（5-HT）再摄取抑制剂），而非马普替林（一种选择性去甲肾上腺素再摄取抑制剂），增强了（±）-曲马多的抗伤害感受作用。总之，我们证明在福尔马林试验的第2阶段，5-羟色胺能途径负责曲马多的抗伤害感受作用，且这种作用由5-HT2受体介导。
