Sacral neuromodulation of nociceptive bladder overactivity in cats.

AIMS: To investigate the effects of electrical stimulation of sacral dorsal/ventral roots on irritation-induced bladder overactivity, reveal possible different mechanisms under nociceptive bladder conditions, and establish a large animal model of sacral neuromodulation. METHODS: Intravesical infusion of 0.5% acetic acid (AA) was used to irritate the bladder and induce bladder overactivity in cats under α-chloralose anesthesia. Electrical stimulation (5, 15, or 30 Hz) was applied to individual S1-S3 dorsal or ventral roots at or below motor threshold intensity. Repeated cystometrograms (CMGs) were performed with/without the stimulation to determine the inhibition of bladder overactivity. RESULTS: AA irritation induced bladder overactivity and significantly (P < 0.05) reduced the bladder capacity to 62.6 ± 11.7% of control capacity measured during saline CMGs. At threshold intensity for inducing reflex twitching of the anal sphincter or toe, S1/S2 dorsal root stimulation at 5 Hz but not at 15 or 30 Hz inhibited bladder overactivity and significantly (P < 0.05) increased bladder capacity to 187.3 ± 41.6% and 155.5 ± 9.7% respectively, of AA control capacity. Stimulation of S3 dorsal root or S1-S3 ventral roots was not effective. Repeated stimulation of S1-S3 dorsal root did not induced a post-stimulation inhibition. CONCLUSIONS: This study established a cat model of sacral neuromodualation of nociceptive bladder overactivity. The results revealed that the mechanisms underlying sacral neuromodulation are different for nociceptive and non-nociceptive bladder activity.

Role of µ, κ, and δ opioid receptors in tibial inhibition of bladder overactivity in cats.

In α-chloralose anesthetized cats, we examined the role of opioid receptor (OR) subtypes (µ, κ, and δ) in tibial nerve stimulation (TNS)-induced inhibition of bladder overactivity elicited by intravesical infusion of 0.25% acetic acid (AA). The sensitivity of TNS inhibition to cumulative i.v. doses of selective OR antagonists (cyprodime for µ, nor-binaltorphimine for κ, or naltrindole for δ ORs) was tested. Naloxone (1 mg/kg, i.v., an antagonist for µ, κ, and δ ORs) was administered at the end of each experiment. AA caused bladder overactivity and significantly (P < 0.01) reduced bladder capacity to 21.1% ± 2.6% of the saline control. TNS at 2 or 4 times threshold (T) intensity for inducing toe movement significantly (P < 0.01) restored bladder capacity to 52.9% ± 3.6% or 57.4% ± 4.6% of control, respectively. Cyprodime (0.3-1.0 mg/kg) completely removed TNS inhibition without changing AA control capacity. Nor-binaltorphimine (3-10 mg/kg) also completely reversed TNS inhibition and significantly (P < 0.05) increased AA control capacity. Naltrindole (1-10 mg/kg) reduced (P < 0.05) TNS inhibition but significantly (P < 0.05) increased AA control capacity. Naloxone (1 mg/kg) had no effect in cyprodime pretreated cats, but it reversed the nor-binaltorphimine-induced increase in bladder capacity and eliminated the TNS inhibition remaining in naltrindole pretreated cats. These results indicate a major role of µ and κ ORs in TNS inhibition, whereas δ ORs play a minor role. Meanwhile, κ and δ ORs also have an excitatory role in irritation-induced bladder overactivity.

Grape Seed Proanthocyanidin Extract Ameliorates Diabetic Bladder Dysfunction via the Activation of the Nrf2 Pathway.

Diabetes Mellitus (DM)-induced bladder dysfunction is predominantly due to the long-term oxidative stress caused by hyperglycemia. Grape seed proanthocyanidin extract (GSPE) has been reported to possess a broad spectrum of pharmacological and therapeutic properties against oxidative stress. However, its protective effects against diabetic bladder dysfunction have not been clarified. This study focuses on the effects of GSPE on bladder dysfunction in diabetic rats induced by streptozotocin. After 8 weeks of GSPE administration, the bladder function of the diabetic rats was improved significantly, as indicated by both urodynamics analysis and histopathological manifestation. Moreover, the disordered activities of antioxidant enzymes (SOD and GSH-Px) and abnormal oxidative stress levels were partly reversed by treatment with GSPE. Furthermore, the level of apoptosis in the bladder caused by DM was decreased following the administration of GSPE according to the Terminal Deoxynucleotidyl Transferase (TdT)-mediated dUTP Nick-End Labeling (TUNEL) assay. Additionally, GSPE affected the expression of apoptosis-related proteins such as Bax, Bcl-2 and cleaved caspase-3. Furthermore, GSPE showed neuroprotective effects on the bladder of diabetic rats, as shown by the increased expression of nerve growth factor (NGF) and decreased expression of the precursor of nerve growth factor (proNGF). GSPE also activated nuclear erythroid2-related factor2 (Nrf2), which is a key antioxidative transcription factor, with the concomitant elevation of downstream hemeoxygenase-1 (HO-1). These findings suggested that GSPE could ameliorate diabetic bladder dysfunction and decrease the apoptosis of the bladder in diabetic rats, a finding that may be associated with its antioxidant activity and ability to activate the Nrf2 defense pathway.