Deciphering Spinal Endogenous Dopaminergic Mechanisms That Modulate Micturition Reflexes in Rats with Spinal Cord Injury

Abstract

Spinal neuronal mechanisms regulate recovered involuntary micturition after spinal cord injury (SCI). It is recently discovered that dopamine (DA) is synthesized in the rat injured spinal cord and is involved in lower urinary tract (LUT) activity. To fully understand the role of spinal DA-ergic machinery in micturition, we examined urodynamic responses in female rats during pharmacological modulation of the DA pathway. Three to four weeks after complete thoracic SCI, L-DOPA administered intravenously during bladder cystometrogram and external urethral sphincter (EUS) electromyography reduced bladder overactivity and increased the duration of EUS bursting, leading to remarkably improved voiding efficiency. Apomorphine, a non-selective dopamine receptor (DR) agonist, or quinpirole, a selective DR 2 agonist, induced similar responses whereas a specific DR 2 antagonist remoxipride alone only had minimal effects. Meanwhile, administration of SCH 23390, a DR 1 antagonist, reduced voiding efficiency by increasing tonic EUS activity and shortening the EUS bursting period. Unexpectedly, SKF 38393, a selective DR 1 agonist, increased EUS tonic activity, implying a complicated role of DR 1 in LUT function.In metabolic cage assays, subcutaneous administration of quinpirole decreased spontaneous voiding frequency and increased voiding volumes; while L-DOPA and apomorphine were inactive possibly due to slow entry into the CNS. Collectively, tonically active DR 1 in SCI rats inhibits urine storage and enhances voiding by differentially modulating the EUS tonic and bursting patterns, respectively; while pharmacologic activation of DR 2 which are normally silent improves voiding by enhancing EUS bursting. Thus, enhancing DA signaling achieves better detrusor-sphincter coordination to facilitate micturition function in SCI rats.

Regional Targeting of Bladder and Urethra Afferents in the Lumbosacral Spinal Cord of Male and Female Rats: A Multiscale Analysis

“…3 A , arrowheads). This region has previously been identified as the location of inhibitory and excitatory interneurons involved in micturition ( Vizzard et al, 1995 ; Araki and de Groat, 1996 ; de Groat et al, 2015 ), some of which express TH ( Hou et al, 2016a , 2021 ; Wiedmann et al, 2021 ). Confocal microscopy confirmed close associations between LUT afferents and TH neurons in this region, however the majority of LUT afferents were not near TH neurons ( Fig.…”

“…One possibility is that local circuit interneurons regulating LUT function extend more rostrally than LUT-regulating preganglionic neurons. Although no chemoarchitectural markers have been identified to delineate this entire group of interneurons, a subpopulation near the SPN expresses TH ( Hou et al, 2016a , 2021 ). In the current study, we found that TH neurons extend more rostrally than preganglionic neurons and we have previously reported that cystometry evokes c-Fos expression in this region and throughout the length of L6 ( Wiedmann et al, 2021 ).…”

Role of Descending Serotonergic Fibers in the Development of Pathophysiology after Spinal Cord Injury (SCI): Contribution to Chronic Pain, Spasticity, and Autonomic Dysreflexia

“…D 2 -like receptors include D 2 , D 3 , and D 4 and they inhibit adenylyl cyclase through G i/o proteins and thus suppress neural activity. Throughout the spinal cord [17] Pronociception [17] Micturition [398,399], cardiovascular function [400],…”

“…Superficial laminae and lamina X [17] Antinociception, pronociception [17] Micturition [398,399] SCH 23390 [398][399][400]402,403], SCH 39166 [401,404] Aripiprazole [405], apomorphine [300,398,400,406], SKF 83959…”

“…Quinpirole [399,402,403,407], Ropinirole [408], sumanirole [409], B-HT 920, bromocriptine [410,411], LY 141865 [412] Remoxipride [398,399], domperidone [400,413], metoclopramide [400],…”