Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados (Cinvestav), Sede Sur, México, DF, Mexico.
Eur J Pharmacol. 2009 Oct 1;619(1-3):25-32. doi: 10.1016/j.ejphar.2009.08.001. Epub 2009 Aug 14.
This study assesses the effects of peripheral or intrathecal pre-treatment or post-treatment with micro, delta, kappa and nociceptin/orphanin FQ (NOP) opioid receptor agonists (morphine, U-50488 [trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide hydrochloride], DADLE [D-Ala2-Leu5-enkephalin] and nociceptin, respectively) on formalin-induced secondary mechanical allodynia and hyperalgesia in rats. 1% Formalin injection produced acute nociceptive behaviors (flinching and licking/lifting) followed by long-term tactile secondary allodynia and hyperalgesia. Neither peripheral (into the formalin-injected paw) nor intrathecal morphine post-treatment reversed formalin-induced secondary allodynia and hyperalgesia. In contrast, morphine pre-treatment prevented the development of these pain behaviors. Intrathecal and peripheral post- but not pre-treatment with U-50488 or DADLE significantly reduced secondary allodynia and hyperalgesia. Interestingly, nociceptin reduced both pain behaviors regardless of the administration site or treatment time. Local antinociceptive effects of morphine, DADLE, U-50488 or nociceptin were blocked by naltrexone, naltrindole, 5-guanidinonaltrindole and [Nphe(1)]nociceptin(1-13)NH(2), respectively. These results suggest that the long-term nociceptive behaviors induced by formalin are differentially modulated by selective opioid receptor agonists. In addition, data suggest that peripheral and spinal delta and kappa opioid receptors are important when nociceptive behaviors are established. In contrast, micro opioid receptors are more important at the beginning of the injury when the sensory system has not changed. NOP receptors participate diminishing both the development and maintenance of nociceptive behaviors. Results suggest that a barrage of afferent input induced by formalin injection initiates a long-term differential change in peripheral and spinal processing that affect the efficacy of opioid receptor agonists.
本研究评估了外周或鞘内预处理或后处理微、德尔塔、kappa 和孤啡肽/孤啡肽 FQ（NOP）阿片受体激动剂（吗啡、U-50488[反式（+/-）-3,4-二氯-N-甲基-N-[2-（1-吡咯烷基）环己基]苯乙酰胺盐酸盐]、DADLE[D-Ala2-Leu5-脑啡肽]和孤啡肽）对福尔马林诱导的大鼠二次机械性痛觉过敏和痛觉过敏的影响。1%福尔马林注射产生急性痛觉行为（退缩和舔/举），随后出现长期触觉二次痛觉过敏和痛觉过敏。外周（注入福尔马林注射的爪子）或鞘内吗啡后处理均不能逆转福尔马林诱导的二次痛觉过敏和痛觉过敏。相比之下，吗啡预处理可防止这些疼痛行为的发展。鞘内和外周后处理而非预处理 U-50488 或 DADLE 显著减轻二次痛觉过敏和痛觉过敏。有趣的是，孤啡肽减轻了这两种疼痛行为，而与给药部位或治疗时间无关。吗啡、DADLE、U-50488 或孤啡肽的局部抗伤害作用分别被纳曲酮、纳洛酮、5-胍基-纳洛酮和[Nphe(1)]孤啡肽（1-13）NH(2)阻断。这些结果表明，福尔马林诱导的长期痛觉行为受选择性阿片受体激动剂的差异调节。此外，数据表明，当伤害感受行为建立时，外周和脊髓德尔塔和 kappa 阿片受体很重要。相比之下，在感觉系统没有改变的受伤初期，微阿片受体更为重要。NOP 受体参与减轻伤害感受行为的发展和维持。结果表明，福尔马林注射引起的传入输入的弹幕引发了外周和脊髓处理的长期差异变化，这影响了阿片受体激动剂的疗效。
