Upregulated 5-HT_1A Receptors Regulate Lower Urinary Tract Function in Rats after Complete Spinal Cord Injury

Spinal cord injury (SCI) above the lumbosacral level often leads to dysfunction of the lower urinary tract (LUT) including detrusor hyper-reflexia, wherein bladder compliance is low, baseline pressures are increased, and filling is accompanied by numerous non-voiding contractions (NVCs) referred to as neurogenic detrusor overactivity. Here, we investigate the expression levels of the serotonin 1A (5-HT_1A) receptor in segments both rostral and caudal to the injured site, as well as the effects on micturition of blocking 5-HT_1A receptor using pharmacological interventions in spinally intact rats or T8 complete SCI rats. The activities of detrusor and external urethral sphincter (EUS) were assessed with the rats in a conscious condition. Adult female rats were divided into two groups: (1) sham control (T8 laminectomy only) and (2) T8 complete spinal cord transection. The observation period was 2 months after the original SCI. In Western blot analyses, we identified significant upregulation of the 5-HT_1A receptor in the T10-L2 and L6/S1 segments after chronic complete SCI. In pharmacological studies, a dose-response study of the 5-HT_1A receptor antagonist, WAY100635, indicated alterations in detrusor and EUS activities in spinally intact rats. Interestingly, blocking the 5-HT_1A receptor alone resulted in inhibitory effects on NVCs with a reduced number and decreased amplitude, but in an increased interval between NVCs in SCI rats. In addition, the duration of EUS bursting was also significantly increased by WAY100635. These inhibitory effects of WAY100635 on NVCs were diminished by subsequent application of a beta-adrenergic blocker (propranolol). The reduction of NVCs observed by WAY100635 may be the result of blocking the constitutive activities of the 5-HT_1A receptor but activating the beta-adrenergic sympathetic pathway, which in turn relaxes bladder activity. Together, the neuroplasticity of the 5-HT_1A receptor can be a potential therapeutic target for treatment of bladder dysfunction after SCI.