Norton Camille S, Neal Charles R, Kumar Suneel, Akil Huda, Watson Stanley J
Mental Health Research Institute, University of Michigan Medical Center, 205 Zina Pitcher Place, Ann Arbor, MI 48109-0720, USA.
J Comp Neurol. 2002 Mar 18;444(4):358-68. doi: 10.1002/cne.10154.
Although nociceptin/orphanin FQ (N/OFQ) influences dopamine (DA) neuronal activity, it is not known whether N/OFQ acts directly on DA neurons, indirectly by means of local circuitry, or both. We used two parallel approaches, dual in situ hybridization (ISH) and neurotoxic lesions of DA neurons by using 6-hydroxydopamine (6-OHDA), to ascertain whether N/OFQ and the N/OFQ receptor (NOP) mRNA are expressed in DA neurons in the ventral tegmental area (VTA) and substantia nigra compacta (SNc). In the VTA and SNc, small populations (approximately 6-10%) of N/OFQ-containing neurons coexpressed mRNA for tyrosine hydroxylase (TH), the rate-limiting enzyme for DA synthesis. Similarly, very few (1-2%) TH-positive neurons contained N/OFQ mRNA signal. A majority of NOP-positive neurons (approximately 75%) expressed TH mRNA and roughly half of the TH-containing neurons expressed NOP mRNA. Many N/OFQ neurons (approximately 50-60%) expressed glutamic acid decarboxylase 65 and 67 mRNAs, markers for gamma-aminobutyric acid (GABA) neurons. In the 6-OHDA lesion studies, NOP mRNA levels were nearly 80 and 85% lower in the VTA and SNc, respectively, on the lesioned side. These lesions appear to lead to compensatory changes, with N/OFQ mRNA levels approximately 60% and 300% higher in the VTA and SNc, respectively, after 6-OHDA lesions. Finally, N/OFQ-stimulated [(35)S]guanylyl-5'-O-(gamma-thio)-triphosphate levels were decreased in the VTA and SNc but not the prefrontal cortex after 6-OHDA lesions. Accordingly, it appears that N/OFQ mRNA was found largely on nondopaminergic (i.e., GABA) neurons, whereas NOP mRNA was located on DA neurons. N/OFQ is in a position to influence DA neuronal activity by means of the NOP located on DA neurons.
尽管痛敏肽/孤啡肽FQ（N/OFQ）会影响多巴胺（DA）神经元的活动，但尚不清楚N/OFQ是直接作用于DA神经元，通过局部神经回路间接起作用，还是两者皆有。我们采用了两种平行方法，即双重原位杂交（ISH）和使用6-羟基多巴胺（6-OHDA）对DA神经元进行神经毒性损伤，以确定N/OFQ和N/OFQ受体（NOP）mRNA是否在腹侧被盖区（VTA）和黑质致密部（SNc）的DA神经元中表达。在VTA和SNc中，一小部分（约6-10%）含有N/OFQ的神经元共表达了酪氨酸羟化酶（TH）的mRNA，TH是DA合成的限速酶。同样，极少（1-2%）的TH阳性神经元含有N/OFQ mRNA信号。大多数NOP阳性神经元（约75%）表达TH mRNA，大约一半含TH的神经元表达NOP mRNA。许多N/OFQ神经元（约50-60%）表达谷氨酸脱羧酶65和67的mRNA，这是γ-氨基丁酸（GABA）能神经元的标志物。在6-OHDA损伤研究中，损伤侧VTA和SNc的NOP mRNA水平分别降低了近80%和85%。这些损伤似乎导致了代偿性变化，6-OHDA损伤后，VTA和SNc中的N/OFQ mRNA水平分别升高了约60%和300%。最后，6-OHDA损伤后，VTA和SNc中N/OFQ刺激的[（35）S]鸟苷-5'-O-（γ-硫代）-三磷酸水平降低，但前额叶皮质未降低。因此，似乎N/OFQ mRNA主要存在于非多巴胺能（即GABA能）神经元上，而NOP mRNA位于DA神经元上。N/OFQ能够通过位于DA神经元上的NOP来影响DA神经元的活动。
