Therapeutic effects of imidazoline 2 receptor activation on lower urinary tract dysfunction in a mouse model of spinal cord injury.

This study evaluated the effects of the imidazoline I2 receptor (I2R) agonist 2-(2-benzofuranyl)-2-imidazoline (2BFI) on lower urinary tract dysfunction (LUTD) in a mouse spinal cord injury (SCI) model. Female mice were divided into three groups: spinal intact (SI), SCI with vehicle, and SCI with 2BFI beginning 2 wk postinjury. SCI was induced by complete Th8-9 spinal transection. Four weeks after SCI, conscious cystometrograms (CMG) and external urethral sphincter (EUS) electromyography (EMG) were recorded. L6-S1 dorsal root ganglia (DRG) were collected for qPCR analysis of TRPV1, tumor necrosis factor α (TNF-α), and inducible nitric oxide synthase (iNOS). In a separate group of animals, intrathecal (i.t.) 2BFI was tested during CMG/EMG in SCI. Organ bath studies assessed 2BFI-induced relaxation in bladder strips precontracted with KCl or carbachol. SCI mice showed increased nonvoiding contractions (NVCs) and reduced voiding efficiency versus SI. 2BFI significantly decreased NVCs, improved voiding efficiency, and prolonged EUS relaxation, evident as reduced EMG activity compared with vehicle. SCI-induced upregulation of TRPV1, TNF-α, and iNOS in DRG was significantly attenuated by 2BFI. I.t. 2BFI reduced residual urine and NVCs and increased EUS relaxation in SCI mice. In organ baths, 2BFI produced significant relaxation of precontracted bladder strips from both SI and SCI mice. I2R activation in the lumbosacral spinal cord and bladder may provide an effective therapeutic strategy for SCI-induced LUTD.NEW & NOTEWORTHY This study shows that selective activation of the imidazoline-2 receptor improves both detrusor overactivity and detrusor-sphincter dyssynergia after spinal cord injury. Systemic and intrathecal administration of 2BFI produced coordinated actions in the spinal cord and lower urinary tract, including enhanced relaxation of the external urethral sphincter, reduced inflammation mediated by C-fiber afferents, and direct relaxation of bladder smooth muscle, indicating a promising therapeutic target.