Delivery of the 5-HT(2A) Receptor Agonist, DOI, Enhances Activity of the Sphincter Muscle during the Micturition Reflex in Rats after Spinal Cord Injury

SIMPLE SUMMARY: Spinal cord injury often disrupts connections between the brain and spinal cord leading to a plethora of health complications, including bladder dysfunction. Spinal cord injured patients are left with symptoms such as a leaky bladder (the inability to hold their urine), frequent urinary tract infections, and potential kidney failure. However, previous studies have shown that manipulation of serotoninergic receptors can improve urinary performance following spinal cord injury. In the current study, we sought to explore how stimulation of a specific serotonergic receptor subtype can significantly enhance bladder function in spinal cord injured rats. To do so, we utilized spinal cord injured female rats that underwent various bladder performance evaluations combined with pharmacological intervention of a specific serotonergic subtype. Additionally, the primary site of action was investigated to determine effects elicited during various administration routes (e.g., directly into the cord, into the femoral vein, or into the skin). Stimulation of this receptor subtype, regardless of delivery route, improved activity of the external urethral sphincter and detrusor-sphincter coordination in spinal cord injured rats. Collectively, the results of these experiments have the potential to provide vital guidance for the development of therapeutic strategies to alleviate urinary dysfunction following spinal cord injury. ABSTRACT: Traumatic spinal cord injury (SCI) interrupts spinobulbospinal micturition reflex pathways and results in urinary dysfunction. Over time, an involuntary bladder reflex is established due to the reorganization of spinal circuitry. Previous studies show that manipulation of serotonin 2A (5-HT(2A)) receptors affects recovered bladder function, but it remains unclear if this receptor regulates the activity of the external urethral sphincter (EUS) following SCI. To elucidate how central and peripheral serotonergic machinery acts on the lower urinary tract (LUT) system, we employed bladder cystometry and EUS electromyography recordings combined with intravenous or intrathecal pharmacological interventions of 5-HT(2A) receptors in female SCI rats. Three to four weeks after a T10 spinal transection, systemic and central blockage of 5-HT(2A) receptors with MDL only slightly influenced the micturition reflex. However, delivery of the 5-HT(2A) receptor agonist, DOI, increased EUS tonic activity and elicited bursting during voiding. Additionally, subcutaneous administration of DOI verified the enhancement of continence and voiding capability during spontaneous micturition in metabolic cage assays. Although spinal 5HT(2A) receptors may not be actively involved in the recovered micturition reflex, stimulating this receptor subtype enhances EUS function and the synergistic activity between the detrusor and sphincter to improve the micturition reflex in rats with SCI.