Curative-like analgesia in a neuropathic pain model:: Parametric analysis of the dose and the duration of treatment with a high-efficacy 5-HT1A receptor agonist
Curative-like analgesia in a neuropathic pain model:: Parametric analysis of the dose and the duration of treatment with a high-efficacy 5-HT1A receptor agonist
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DOI：
10.1016/j.ejphar.2007.04.022
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发表时间：
2007-07-30
影响因子：
5
通讯作者：
Colpaert, Francis C.
中科院分区：
文献类型：
--
作者：
Deseure, Kristof;Breand, Sophie;Colpaert, Francis C.
通过最近发现的选择性 5-HT1A 受体配体 F 13640 L(3-氯-4-氟-苯基)-[4-氟-4-1[(5-甲基-吡啶-2-基甲基)-氨基]甲基哌啶-1-基]甲酮，富马酸盐]高效激活中枢 5-HT1A 受体，在急性和慢性大鼠模型中产生前所未有的广谱镇痛作用伤害性疼痛和神经性疼痛；它对于阿片类药物无效、诱导镇痛耐受或引起持续性痛觉过敏/异常性疼痛的情况也有效。与吗啡的作用相反，F 13640 的（“类治疗”）镇痛作用在治疗停止后仍然持续存在。在这里，我们一方面检查了 F 13640 治疗的剂量和持续时间与另一方面持续镇痛持续时间之间的关系（如果有的话）。大鼠受到单侧眼眶内神经损伤并出现异常性疼痛（通过 24 天内对 von Frey 丝刺激的反应增强来评估），此后在两个实验中使用渗透泵向大鼠皮下注射 F 13640。其中一种是按 0.04-10 毫克/天的剂量进行为期一周的输注；在第二个实验中，实施0.63毫克/天的剂量，持续时间从1天到56天。这些250倍和56倍的剂量和治疗持续时间的变化分别导致治疗后持续镇痛约10天和40天。 F 13640 治疗的持续时间至少与剂量一样多，决定了 F 13640 诱导的持续镇痛。突触前和突触后、大脑和脊髓 5-HT1A 受体的神经适应性调节可能与高效 5-HT1A 受体激活引起的镇痛作用的动态、剂量和时间依赖性、治疗前上升和治疗后衰减有关。 (C) 2007 Elsevier B.V. 保留所有权利。
High-efficacy activation of central 5-HT1A receptors by means of the recently discovered, selective 5-HT1A receptor ligand, F 13640 L(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-1[(5-methyl-pyridin-2-ylmethyl)-amino]methyl piperidin-1-yl]methanone, fumaric acid salt] causes an unprecedented, broad-spectrum analgesia in rat models of acute and chronic pain of nociceptive and neuropathic origin; it also is effective in conditions where opioids either are ineffective, induce analgesic tolerance, or elicit persistent hyperalgesia/allodynia. Inversely mirroring morphine's actions, F 13640's ("curative-like") analgesic effects persist after the discontinuation of treatment. Here, we examined the relationships, if any, between the dose and the duration of F 13640 treatment on the one hand, and the duration of persistent analgesia on the other. Rats received unilateral intraorbital nerve injury and developed allodynia - as assessed by an increased response to von Frey filament stimulation within 24 days-, thereafter, using osmotic pumps, rats were subcutaneously infused with F 13640 in two experiments. In one, a one-week infusion was instituted at 0.04-10-mg/day doses; in a second experiment, a 0.63-mg/day dose was implemented for a duration ranging from I to 56 days. These 250- and 56-fold variations of the dose and duration of treatment caused post-treatment, persistent analgesia for about 10 and 40 days, respectively. At least as much as dose, the duration of F 13640 treatment determines F 13640-induced persistent analgesia. Neuroadaptive modulations at pre- and postsynaptic, brain and spinal cord 5-HT1A receptors may be involved in the dynamical, dose- and time-dependent, pretreatment rise and post-treatment decay of the analgesia induced by high-efficacy 5-HT1A receptor activation. (C) 2007 Elsevier B.V. All rights reserved.