Development of urinary impairment after spinal cord injury courses with altered urethral serotonin signalling in the female mice.

Spinal Cord Injury (SCI) often leads to urinary incontinence. While alterations in the bladder have been considered the primary cause of post-SCI urinary dysfunction, evidence suggests that urethral afferents may influence post-SCI bladder activity. These afferents respond to locally produced serotonin (5-HT), and 5-HT signalling may likely be affected by SCI. Here, we investigated the role of urethral 5-HT on post-SCI bladder reflex activity using female C57BL/6 mice (wild-type -WT- and animals lacking urethral 5-HT (tryptophan hydroxylase 1 -tph1- null -tph1(-/-)). In WT animals, bladder overactivity and increased 5-HT(+) urethral cells were observed at one and four weeks post-SCI (1w and 4w, respectively), while, in contrast, tph1(-/-) mice showed some preservation of bladder function. Both genotypes developed urethral smooth muscle atrophy 4w post-SCI, but fibrosis of striated muscle was detected only in tph1(-/-) 4w SCI mice. Sensory and cholinergic fibres were upregulated only in WT SCI mice, suggesting 5-HT depletion may block their expansion. Pharmacological blockade of 5-HT receptors did not prevented urinary impairment but affected SCI-induced bladder dysfunction. These observations indicate that urethral 5-HT contributes to SCI-induced urinary impairment and urethral tissue reorganization, offering new insights into the urethrovesical reflex and potentially pinpointing new therapeutic targets.