ObjectivesTo investigate the effect of descending serotonergic and noradrenergic pathways on nociception in the lower urinary tract (LUT). MethodsFemale Sprague-Dawley rats were used. Following intraperitoneal administration of Vehicle or Milnacipran (30mg/kg), which is one of serotonin-noradrenaline reuptake inhibitors (SNRI), 0.1% AA was infused into the bladder in normal (n=4, each) and spinal cord injury (SCI) (n=4, each) rats for 2h on consciousness, and c-Fos, 5-HT and DH were stained using immunohistochemistry at the L6 spinal cord as spinal areas associated with LUT. ResultsIn SCI rats, 5-HT or DH-positive fibers were not observed at the L6 spinal cord, while there were many 5-HT and DH-positive fibers in normal rats. The total number of c-Fos-positive cells was significantly increased in SCI rats compared to Normal rats (209.47.1 in Normal, 336.4 +/- 28.9 in SCI, P < 0.05), which indicated that interruption of supraspinal modulation enhances nocieptive transmission in the LUT. Regarding the effect of Milnacipran administration, the number of c-Fos-positive cells was significantly decreased at all region of the L6 spinal cord in normal rats (P < 0.05), while this reduction was not observed in SCI rats. This result demonstrated that administration of SNRI attenuates nocieptive transmission in the LUT, indicating that 5-HT and noradrenaline work as mediators of endogenous analgesic mechanisms through the supraspinal descending pain pathways. ConclusionsSupraspinal projections of descending serotonergic and noradrenergic pathways to the lower lumbar spinal cord modulate nocieptive transmission in the LUT. Administration of SNRI attenuates nocieptive transmission in the LUT, which could result from enhancement of modulating descending serotonergic and noradrenergic pathways.