Effects of acute sacral neuromodulation on bladder reflex in complete spinal cord injury rats.

BACKGROUND: Neurogenic bladder associated with spinal cord injury (SCI) often results in serious disruption of lower urinary tract function. Compared to conventional therapies, sacral neuromodulation (SNM) may offer an alternative, non-destructive treatment for SCI patients with bladder dysfunction. Understanding bladder reflex changes following SCI and the effects of SNM may yield new insights for innovative use of this promising technique. Using a SCI rat model developed in this study, we investigated: 1) the bladder responses with different grades of bladder filling in intact and SCI rats; and 2) the effects of acute SNM on bladder reflex responses in SCI rats. METHODS: An SCI rat model with overactive bladder was developed and evaluated in this study to examine the effects of acute SNM on bladder reflex in complete SCI rats. Twelve adult female Sprague-Dawley rats were divided into three groups; group I: spinally intact rats (N = 4), group II: transected (T9-T10) rats (N = 4), i.e., SCI rats, and group III: SCI rats with SNM treatment (N = 4). All rats were anesthetized and set up for continuous saline infusion. Cystometric parameters, including contraction period, contraction duration, bladder peak pressure, and number of uninhibited contractions, were analyzed and compared between groups and between conditions with and without SNM treatment for SCI rats. RESULTS: In the intact rats, the frequency of bladder contraction was dependent upon the rate of bladder filling, while the spinal transected rats exhibited large fluctuation and demonstrated different patterns in response to saline infusion. Moreover, the bladder in SCI rats demonstrated an increased contraction period and a decreased contraction strength compared to the intact rats (all p < 0.05). In SCI rats under acute SNM treatment, bladder contraction period and duration tended to become longer, and the bladder peak pressure was decreased. The accumulating evidence indicated that acute SNM had inhibiting effects for bladder overactivity following SCI. CONCLUSION: The spinal rat model developed in this study was suitable to investigate the effect of sacral neural stimulation on micturition reflex. The results of present study demonstrated that the micturition reflex can be modulated by sacral neural stimulation.

Kv3 Channels Contribute to the Excitability of Subpopulations of Spinal Cord Neurons in Lamina VII.

Autonomic parasympathetic preganglionic neurons (PGNs) drive contraction of the bladder during micturition but remain quiescent during bladder filling. This quiescence is postulated to be because of recurrent inhibition of PGN by fast-firing adjoining interneurons. Here, we defined four distinct neuronal types within Lamina VII, where PGN are situated, by combining whole cell patch clamp recordings with k-means clustering of a range of electrophysiological parameters. Additional morphologic analysis separated these neuronal classes into parasympathetic preganglionic populations (PGN) and a fast-firing interneuronal population. Kv3 channels are voltage-gated potassium channels (Kv) that allow fast and precise firing of neurons. We found that blockade of Kv3 channels by tetraethylammonium (TEA) reduced neuronal firing frequency and isolated high-voltage-activated Kv currents in the fast-firing population but had no effect in PGN populations. Furthermore, Kv3 blockade potentiated the local and descending inhibitory inputs to PGN indicating that Kv3-expressing inhibitory neurons are synaptically connected to PGN. Taken together, our data reveal that Kv3 channels are crucial for fast and regulated neuronal output of a defined population that may be involved in intrinsic spinal bladder circuits that underpin recurrent inhibition of PGN.

Excitatory and inhibitory effects of stimulation of sacral dorsal root ganglion on bladder reflex in cats.

PURPOSE: To explore the effects of electrical stimulation of the sacral dorsal root ganglion (DRG) on bladder reflexes in α-chloralose-anesthetized cats. METHODS: Bladder activity was recorded under isovolumetric conditions. A pair of hook electrodes was placed in the right S1 and S2 DRGs of 12 adult male cats, which were stimulated over a range of frequencies (0.25-30 Hz) and at threshold intensity. RESULTS: Stimulation of S1 and S2 DRGs inhibited or evoked bladder contractions under isovolumetric conditions depending on the frequency of stimulation in nine cats. Stimulation at low frequencies (3-7 Hz on S1 or S2 DRG) significantly inhibited isovolumetric rhythmic bladder contractions, while excitatory effects were observed at two frequency ranges, including lower frequencies (0.25-1.5 Hz on S1 DRG and 0.25-1.25 Hz on S2 DRG) and middle frequencies (15-30 Hz on S1 and S2 DRGs). CONCLUSIONS: These results suggest that the sacral DRG might be a potential valuable target for electrical stimulation in the treatment of bladder dysfunction.

Influence of urothelial or suburothelial cholinergic receptors on bladder reflexes in chronic spinal cord injured cats.

The effects of intravesical administration of a muscarinic receptor agonist (oxotremorine-M, OXO-M) and antagonist (atropine methyl nitrate, AMN) and of a nicotinic receptor agonist (nicotine) and antagonist (hexamethonium, C6) on reflex bladder activity were investigated in conscious female chronic spinal cord injured (SCI) cats using cystometry. OXO-M (50µM) decreased bladder capacity (BC) for triggering micturition contractions, increased maximal micturition pressure (MMP), increased frequency and area under the curve of pre-micturition contractions (PMC-AUC). Nicotine (250µM) decreased BC, increased MMP, but did not alter PMC-AUC. The effects of OXO-M on BC and PMC-AUC were suppressed by intravesical administration of AMN (50-100µM), and the effects of nicotine were blocked by hexamethonium (1mM). Antagonists infused intravesically alone did not alter reflex bladder activity. However, AMN (0.2mg/kg, subcutaneously) decreased PMC-AUC. 8-OH-DPAT (0.5mg/kg, s.c.), a 5-HT1A receptor agonist, suppressed the OXO-M-induced decrease in BC but not the enhancement of PMC-AUC. These results indicate that activation of cholinergic receptors located near the lumenal surface of the bladder modulates two types of reflex bladder activity (i.e., micturition and pre-micturition contractions). The effects may be mediated by activation of receptors on suburothelial afferent nerves or receptors on urothelial cells which release transmitters that can in turn alter afferent excitability. The selective action of nicotine on BC, while OXO-M affects both BC and PMC-AUC, suggests that micturition reflexes and PMCs are activated by different populations of afferent nerves. The selective suppression of the OXO-M effect on BC by 8-OH-DPAT without altering the effect on PMCs supports this hypothesis. The failure of intravesical administration of either AMN or hexamethonium alone to alter bladder activity indicates that cholinergic receptors located near the lumenal surface do not tonically regulate bladder reflex mechanisms in the SCI cat.