The controversy about spinal neuronal nitric oxide synthase: under which conditions is it up- or downregulated?

In recent years, the regulation of the synthesis of nitric oxide (NO) in the central nervous system has attracted much interest because it has been shown that NO is involved in a wide variety of functions such as neuroprotection, neurotoxicity, neurotransmission, and neuroplasticity under physiological and pathophysiological conditions. However, the use of different detection techniques for neuronal nitric oxide synthase (nNOS), different animal species, and different experimental lesions has led to contradictory results concerning the direction of changes in spinal nNOS expression. This paper summarizes the available data on the expression on nNOS in the spinal cord under physiological and pathological conditions and tries to extract some of the basic mechanisms that underlie neuronal up- or downregulation of this enzyme. Wherever possible, results obtained with the NADPH-dependent diaphorase reaction are also included for reasons of comparison. The main conclusion is that changes in spinal nNOS expression critically depend on the type of afferent fibres activated by a specific lesion as well as the intensity and duration of input to the spinal cord. This input may be further modified by supraspinal influences. Thus the exact composition of these factors, which is undoubtfully highly variable between different experimental models, appears to determine whether the spinal NO system responds with an up- or downregulation of nNOS expression or in a bidirectional way. With regard to the diaphorase reaction it is becoming increasingly clear that under pathological conditions data obtained with this reaction differ markedly from those obtained with immunohistochemical visualization of nNOS.