Monoamine-Dependent, Opioid-Independent Antihypersensitivity Effects of Intrathecally Administered Milnacipran, a Serotonin Noradrenaline Reuptake Inhibitor, in a Postoperative Pain Model in Rats
Monoamine-Dependent, Opioid-Independent Antihypersensitivity Effects of Intrathecally Administered Milnacipran, a Serotonin Noradrenaline Reuptake Inhibitor, in a Postoperative Pain Model in Rats
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DOI：
10.1124/jpet.110.168336
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发表时间：
2010-09-01
影响因子：
3.5
通讯作者：
Saito, Shigeru
中科院分区：
文献类型：
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作者：
Obata, Hideaki;Kimura, Masafumi;Saito, Shigeru
神经递质5-羟色胺（5-HT）和去甲肾上腺素（NA）在抑制脊髓中的伤害性传递中具有重要作用。在本研究中，我们确定了米那普仑，5-羟色胺和NA再摄取抑制剂（SNRI），在术后疼痛的大鼠模型的脊髓中的抗过敏作用的疗效和性质。在所有实验中使用Sprague-Dawley大鼠。在后爪的足底面上做一个切口。通过测定对应用于爪的von Frey细丝的撤回阈值来测量机械超敏反应。在爪切口后24小时鞘内施用药物。还进行了腰脊髓背角的微透析研究，以测量全身注射米那普仑后的5-HT和NA水平。米那普仑（1-30 μ g）产生剂量依赖性抗过敏作用。注射30 μ g后，作用持续6 h。30微克或更少的剂量没有产生异常行为。10 μ g米那普仑的峰值抗过敏作用被μ 2-肾上腺素受体（咪唑克生; 30 μ g）或5-HT受体（麦角新碱; 30 μ g）的拮抗剂鞘内预处理阻断。鞘内预处理与30微克纳洛酮，μ阿片受体拮抗剂，并没有逆转米那普仑的效果。等效辐射分析表明米那普仑和吗啡之间的抗伤害性协同作用。微透析研究表明，米那普仑增加脊髓背角5-HT和NA水平。这些发现表明，鞘内注射米那普仑在术后疼痛模型中的抗超敏反应作用是单胺介导的。SNRI与吗啡联合给药可能是抑制术后过敏的一种有前途的治疗方法。
The neurotransmitters serotonin (5-HT) and noradrenaline (NA) have important roles in suppressing nociceptive transmission in the spinal cord. In the present study, we determined the efficacy and nature of the antihypersensitivity effects of milnacipran, a 5-HT and NA reuptake inhibitor (SNRI), in the spinal cord in a rat model of postoperative pain. Sprague-Dawley rats were used in all experiments. An incision was made on the plantar aspect of the hind paw. Mechanical hypersensitivity was measured by determining the withdrawal threshold to von Frey filaments applied to the paw. Drugs were administered intrathecally 24 h after paw incision. Microdialysis studies of the dorsal horn of the lumbar spinal cord were also performed to measure 5-HT and NA levels after systemic injection of milnacipran. Milnacipran (1-30 mu g) produced dose-dependent antihypersensitivity effects. The effect lasted 6 h after the 30-mu g injection. Doses of 30 mu g or less produced no abnormal behavior. The peak antihypersensitivity effect of 10 mu g of milnacipran was blocked by intrathecal pretreatment with antagonists of the mu 2-adrenoceptor (idazoxan; 30 mu g) or 5-HT receptors (methysergide; 30 mu g). Intrathecal pretreatment with 30 mu g of naloxone, a mu-opioid receptor antagonist, did not reverse the effect of milnacipran. Isobolographic analysis indicated antinociceptive synergism between milnacipran and morphine. Microdialysis studies revealed that milnacipran increased both 5-HT and NA levels in the spinal dorsal horn. These findings suggest that the antihypersensitivity effect of intrathecal milnacipran in the postoperative pain model is monoamine- mediated. Combined administration of an SNRI with morphine might be a promising treatment to suppress postoperative hypersensitivity.