Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy.
Exp Neurol. 2011 Mar;228(1):126-37. doi: 10.1016/j.expneurol.2010.12.024. Epub 2011 Jan 6.
Nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor antagonists proved to be effective in alleviating experimental parkinsonism. Nonetheless, loss of effectiveness or even worsening of parkinsonian symptoms have been observed at high doses. With the aim of clarifying the circuitry underlying the dual action of NOP receptor antagonists and the role of endogenous dopamine, the NOP receptor antagonist 1-benzyl-N-[3-[spiroisobenzofuran-1(3H),4'-piperidin-1-yl]propyl]pyrrolidine-2-carboxamide (Compound 24) and the D(2)/D(3) receptor antagonist raclopride were used in 6-hydroxydopamine hemilesioned rats. Systemically administered Compound 24 improved motor activity in the 0.1-10mg/kg dose range being ineffective at 30 mg/kg. To confirm NOP selectivity, Compound 24 improved motor performance in wild-type mice at 1 and 10mg/kg and inhibited it at 60 mg/kg, being ineffective in NOP receptor knockout mice. To prove that the bell-shaped profile was mediated by nigral NOP receptors, reverse dialysis of Compound 24 (0.03 μM) in substantia nigra reticulata ameliorated akinesia whereas Compound 24 (3 μM) was ineffective. To demonstrate that motor responses were mediated by tuning inhibitory and excitatory inputs to nigro-thalamic neurons, the low concentration elevated GABA and reduced glutamate in substantia nigra, simultaneously reducing GABA levels in ventro-medial thalamus. Conversely, the higher concentration reduced nigral and elevated thalamic GABA, without affecting nigral glutamate levels. Co-perfusion with raclopride (1 μM) abolished the antiakinetic action of Compound 24 (0.03 μM) and turned the ineffectiveness of Compound 24 (3 μM) into an antiakinetic effect. The low concentration reduced nigral but did not affect thalamic GABA whereas the higher concentration elevated nigral and reduced thalamic GABA. Neither concentration affected nigral glutamate. We conclude that dual motor effects of Compound 24 in hemiparkinsonian rats are accomplished through blockade of nigral NOP receptors resulting in opposite modulation of nigro-thalamic neurons. Endogenous dopamine contributes to these responses affecting the level of GABAergic inhibition of the nigral output via D(2)/D(3) receptors.
孤啡肽/孤啡肽 FQ（N/OFQ）肽（NOP）受体拮抗剂已被证明可有效缓解实验性帕金森病。然而，在高剂量下，其有效性会降低甚至帕金森病症状恶化。为了阐明 NOP 受体拮抗剂双重作用的潜在机制以及内源性多巴胺的作用，NOP 受体拮抗剂 1-苄基-N-[3-[螺异苯并呋喃-1（3H），4'-哌啶基]丙基]吡咯烷-2-羧酰胺（化合物 24）和 D2/D3 受体拮抗剂雷氯必利被用于 6-羟多巴胺半侧损伤大鼠中。系统给予化合物 24 可改善 0.1-10mg/kg 剂量范围内的运动活动，而 30mg/kg 剂量无效。为了证实 NOP 受体选择性，化合物 24 在野生型小鼠中在 1mg/kg 和 10mg/kg 剂量下改善运动表现，而在 60mg/kg 剂量下抑制运动表现，在 NOP 受体敲除小鼠中无效。为了证明钟形曲线是由黑质 NOP 受体介导的，黑质网状部的化合物 24（0.03μM）的逆行透析改善了运动不能，而化合物 24（3μM）无效。为了证明运动反应是通过调节黑质-丘脑神经元的抑制性和兴奋性输入来介导的，低浓度增加了黑质中的 GABA 并减少了谷氨酸，同时减少了腹侧内侧丘脑中的 GABA 水平。相反，较高的浓度降低了黑质和升高了丘脑 GABA，而不影响黑质中的谷氨酸水平。与雷氯必利（1μM）共灌注消除了化合物 24（0.03μM）的抗运动不能作用，并将化合物 24（3μM）的无效作用转化为抗运动不能作用。低浓度降低了黑质中的 GABA，但不影响丘脑中的 GABA，而高浓度升高了黑质中的 GABA，降低了丘脑中的 GABA。两种浓度都不影响黑质中的谷氨酸。我们得出结论，化合物 24 在半帕金森病大鼠中的双重运动作用是通过阻断黑质 NOP 受体来实现的，从而导致黑质-丘脑神经元的相反调节。内源性多巴胺通过 D2/D3 受体影响黑质输出的 GABA 抑制水平，从而对这些反应做出贡献。
