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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.

c-Fos expression was studied in the lumbar and sacral spinal cord regions involved in processing afferent input from the lower urinary tract and a comparison was made between spinal cord-injured (SCI) animals and control animals with intact neuraxes. Afferent pathways from the lower urinary tract were activated either by insertion of a catheter through the urethra into the urinary bladder or by catheterisation plus induction of reflex micturition contractions by intravesical saline infusion. Placement of a catheter alone elicited Fos expression in a similar number of neurones in SCI and control rats mainly in the medial dorsal horn (MDH) and dorsal commissure (DCM) in the segments L1-2 and L5-S1 with a maximum in L5. Additional saline infusion induced low-frequency, high-amplitude, rhythmic bladder contractions of long duration in the rats with intact spinal cords, whereas in SCI rats, bladder distension elicited reflex contractions at a higher frequency, smaller amplitude and shorter duration. However, the basal and mean bladder pressure, as well as the total contraction time relative to the whole recording time, was not significantly different. Distension-induced bladder contractions markedly increased Fos expression primarily in the spinal segments L5-S1 in the control rats, where the majority of bladder and urethral afferent fibres terminates. Fos-positive cells were located in the MDH, lateral dorsal horn (LDH), DCM and the lateral aspect of laminae V-VII. Compared to controls, Fos expression after spinal cord injury (SCI) occurred in a significantly greater number of neurones throughout the segments L3-S1 following induction of bladder reflexes. The greatest proportional increase in the number of Fos-positive cells occurred in L3-5 which normally receive only little afferent input from the urinary bladder. Cell numbers predominantly increased in the LDH and lateral lamina V-VII. The data are consistent with the concept of a neuroplastic reorganisation of spinal pathways after SCI. Unmasking of silent synapses or formation of new connections by afferent axonal sprouting caudal to the lesion, as evident from the increased numbers of cells expressing Fos after bladder distension, could be factors underlying the emergence of reflexogenic micturition in chronic SCI rats.

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