Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, via Fossato di Mortara 17-19, 44100 Ferrara, Italy.
Neuroscience. 2010 Mar 10;166(1):40-8. doi: 10.1016/j.neuroscience.2009.12.006. Epub 2009 Dec 13.
The contribution of endogenous nociceptin/orphanin FQ (N/OFQ) to neuroleptic-induced parkinsonism has been evaluated in haloperidol-treated mice. Pharmacological blockade of N/OFQ receptors (NOP) via systemic administration of 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H benzimidazol-2-one (J-113397, 0.01-10 mg/kg i.p.) or central injection of [Nphe(1),Arg(14),Lys(15)]N/OFQ-NH(2) (UFP-101, 10 nmol i.c.v.) attenuated (0.8 mg/kg) haloperidol-induced motor deficits as evaluated by a battery of behavioral tests providing complementary information on motor parameters: the bar, drag and rotarod tests. A combined neurochemical and behavioral approach was then used to investigate whether the substantia nigra reticulata could be involved in antiakinetic actions of J-113397. Microdialysis combined to the bar test revealed that haloperidol (0.3 and 0.8 mg/kg i.p.) caused a dose-dependent and prolonged elevation of immobility time (i.e. akinesia) which was associated with an increase in nigral glutamate and a reduction in GABA release. Conversely, J-113397 (1 mg/kg) alone reduced glutamate and elevated nigral GABA release, and when challenged against haloperidol, counteracted its behavioral and neurochemical effects. Microdialysis coupled to behavioral testing also demonstrated that NOP receptor knockout mice were resistant to haloperidol (0.3 mg/kg) compared to wild-type mice, lack of response being associated with a reversal of glutamate release facilitation into inhibition and no change in nigral GABA release. This study provides pharmacological and genetic evidence that endogenous N/OFQ contributes to haloperidol-induced akinesia and changes of amino acid transmission in mice. Moreover, it confirms the view that NOP receptor antagonists are capable of reversing akinesia across species and genotypes and may prove effective in relieving neuroleptic-induced parkinsonism.
内源性孤啡肽（N/OFQ）对神经安定剂诱导的帕金森病的作用已经在氟哌啶醇处理的小鼠中进行了评估。通过系统给予 1-[(3R,4R)-1-环辛基甲基-3-羟甲基-4-哌啶基]-3-乙基-1,3-二氢-2H 苯并咪唑-2-酮（J-113397，0.01-10mg/kg 腹腔注射）或中央注射[Nphe(1),Arg(14),Lys(15)]N/OFQ-NH(2)（UFP-101，10nmol 脑室注射）来阻断 N/OFQ 受体（NOP），可以减轻（0.8mg/kg）氟哌啶醇诱导的运动障碍，这通过一系列行为测试来评估，这些测试提供了有关运动参数的互补信息：棒测试、拖曳测试和转棒测试。然后，采用神经化学和行为相结合的方法来研究黑质网状部是否参与了 J-113397 的抗运动不能作用。微透析与棒测试相结合显示，氟哌啶醇（0.3 和 0.8mg/kg 腹腔注射）引起剂量依赖性和持久的运动不能时间（即运动不能）升高，这与黑质谷氨酸增加和 GABA 释放减少有关。相反，J-113397（1mg/kg）单独降低谷氨酸并增加黑质 GABA 释放，当与氟哌啶醇对抗时，拮抗其行为和神经化学作用。微透析与行为测试相结合还表明，与野生型小鼠相比，NOP 受体敲除小鼠对氟哌啶醇（0.3mg/kg）具有抗性，缺乏反应与谷氨酸释放从易化到抑制的逆转有关，而黑质 GABA 释放没有变化。这项研究提供了药理学和遗传学证据，表明内源性 N/OFQ 有助于氟哌啶醇诱导的运动不能和小鼠氨基酸传递的变化。此外，它证实了 NOP 受体拮抗剂能够在跨物种和基因型中逆转运动不能的观点，并且可能在缓解神经安定剂诱导的帕金森病方面有效。
