Involvement of opioid receptors in inhibition of bladder overactivity induced by foot stimulation in cats.

PURPOSE: We examined the role of opioid receptors in the inhibition of bladder overactivity induced by electrical stimulation of the foot. MATERIALS AND METHODS: Experiments were done in 6 cats under α-chloralose anesthesia when the bladder was infused with saline or 0.25% acetic acid. Naloxone (1 mg/kg intravenously) was administered to block opioid receptors. To modulate reflex bladder activity electrical stimulation (5 Hz, 0.2 millisecond pulse width) was applied to the foot via skin surface electrodes at intensities of multiple times the threshold needed to induce observable toe movement. RESULTS: Acetic acid irritated the bladder, induced bladder overactivity and significantly decreased bladder capacity to a mean ± SE 25.3% ± 5.9% that of saline control capacity (p = 0.0001). Foot stimulation at 4T suppressed acetic acid induced bladder overactivity and significantly increased bladder capacity to 47.1% ± 5.9% of control (p = 0.0007). Naloxone did not significantly change bladder capacity during acetic acid irritation but it completely eliminated the inhibition of bladder overactivity induced by foot stimulation. CONCLUSIONS: Results indicate that opioid receptors have an important role in foot afferent inhibition of bladder overactivity. This raises the possibility that opioid receptors might be used as a pharmacological target to enhance the efficacy of foot stimulation for inhibiting bladder overactivity.

Inhibition of bladder overactivity by a combination of tibial neuromodulation and tramadol treatment in cats.

Our recent study in cats revealed that inhibition of bladder overactivity by tibial nerve stimulation (TNS) depends on the activation of opioid receptors. TNS is a minimally invasive treatment for overactive bladder (OAB), but its efficacy is low. Tramadol (an opioid receptor agonist) is effective in treating OAB but elicits significant adverse effects. This study was to determine if a low dose of tramadol (expected to produce fewer adverse effects) can enhance the TNS inhibition of bladder overactivity. Bladder overactivity was induced in α-chloralose-anesthetized cats by an intravesical infusion of 0.25% acetic acid (AA) during repeated cystometrograms (CMGs). TNS (5 Hz) at two to four times the threshold intensity for inducing toe movement was applied during CMGs before and after tramadol (0.3-7 mg/kg iv) to examine the interaction between the two treatments. AA irritation significantly reduced bladder capacity to 24.8 ± 3.3% of the capacity measured during saline infusion. TNS alone reversibly inhibited bladder overactivity and significantly increased bladder capacity to 50-60% of the saline control capacity. Tramadol administered alone in low doses (0.3-1 mg/kg) did not significantly change bladder capacity, whereas larger doses (3-7 mg/kg) increased bladder capacity (50-60%). TNS in combination with tramadol (3-7 mg/kg) completely reversed the effect of AA. Tramadol also unmasked a prolonged (>2 h) TNS inhibition of bladder overactivity that persisted after termination of the stimulation. The results suggest a novel treatment strategy for OAB by combining tibial neuromodulation with a low dose of tramadol, which is minimally invasive with a potentially high efficacy and fewer adverse effects.

Differential role of opioid receptors in tibial nerve inhibition of nociceptive and nonnociceptive bladder reflexes in cats.

Naloxone (an opioid receptor antagonist) was used to examine the role of opioid mechanisms in bladder reflexes and in somatic afferent inhibition of these reflexes by tibial nerve stimulation (TNS). Experiments were conducted in α-chloralose-anesthetized cats when the bladder was infused with saline or 0.25% acetic acid (AA). The bladder volume was measured at the first large-amplitude (>30 cmH(2)O) contraction during a cystometrogram and termed "estimated bladder capacity" (EBC). AA irritated the bladder, induced bladder overactivity, and significantly (P < 0.0001) reduced EBC to 14.3 ± 1.9% of the saline control. TNS (5 Hz, 0.2 ms) at 4 and 8 times the threshold (T) intensity for inducing an observable toe movement suppressed AA-induced bladder overactivity and significantly increased EBC to 41.5 ± 9.9% (4T, P < 0.05) and 46.1 ± 7.9% (8T, P < 0.01) of the saline control. Naloxone (1 mg/kg iv) completely eliminated TNS inhibition of bladder overactivity. Naloxone (0.001-1 mg/kg iv) did not change EBC during AA irritation. However, during saline infusion naloxone (1 mg/kg iv) significantly (P < 0.01) reduced EBC to 66.5 ± 8.1% of the control EBC. During saline infusion, TNS induced an acute increase in EBC and an increase that persisted following the stimulation. Naloxone (1 mg/kg) did not alter either type of inhibition. However, naloxone administered during the poststimulation inhibition decreased EBC. These results indicate that opioid receptors have different roles in modulation of nociceptive and nonnociceptive bladder reflexes and in somatic afferent inhibition of these reflexes, raising the possibility that opioid receptors may be a target for pharmacological treatment of lower urinary tract disorders.

Post-stimulation inhibitory effect on reflex bladder activity induced by activation of somatic afferent nerves in the foot.

PURPOSE: We determined whether transcutaneous electrical stimulation of somatic afferent nerves in the foot of cats would induce a post-stimulation increase in bladder capacity. MATERIALS AND METHODS: In 12 α-chloralose anesthetized cats electrical stimulation (5 Hz) was applied to the skin of the hind foot for 2, 30-minute periods via dual pad electrodes attached on the plantar and dorsal surfaces (combination 1 and 2) or at 2 sites on the plantar surface (combination 1 and 3). The post-stimulation effect was examined by repeat cystometrogram after 30-minute stimulation. In the control group of 12 cats isovolumetric contractions were allowed to continue during each 30-minute period without stimulation. RESULTS: Stimulation inhibited isovolumetric rhythmic bladder contractions. Bladder capacity was not increased after the first 30-minute foot stimulation via electrodes 1 and 2 but it was significantly increased a mean ± SE of 47.5% ± 2.9% after the second 30-minute stimulation via electrodes 1 and 3. After inducing the post-stimulation effect the foot stimulation applied during cystometrograms via electrodes 1 and 2 or 1 and 3 elicited a further increase in bladder capacity (mean 23.26% ± 17.64% and 20.07% ± 18.59%, respectively). CONCLUSIONS: Results show that the transcutaneous plantar electrical stimulation of somatic afferent nerves in the foot can induce a post-stimulation increase in bladder capacity, suggesting that an intermittent stimulation pattern rather than continuous stimulation might be effective as clinical application to treat overactive bladder symptoms.

Involvement of metabotropic glutamate receptor 5 in pudendal inhibition of nociceptive bladder activity in cats.

This study used MTEP, a metabotropic glutamate receptor 5 (mGluR5) antagonist, to examine the role of mGluR5 in the neural control of the urinary bladder and in the inhibition of the micturition reflex by pudendal nerve stimulation (PNS). Experiments were conducted in 11 female cats under α-chloralose anaesthesia when the bladder was infused with either saline or 0.25% acetic acid (AA). AA irritated the bladder, induced bladder overactivity and significantly (P < 0.001) reduced bladder capacity to 14.9 ± 10.3% of the saline control capacity. MTEP (0.1-50 mg kg(-1), i.v.) significantly (P < 0.05) increased bladder capacity during saline distension but not during AA irritation. However, MTEP induced a transient inhibition of isovolumetric bladder contractions under both conditions. PNS (5 Hz), which was tested at the threshold (T) intensity for inducing a complete inhibition of isovolumetric bladder contractions and at an intensity of 3-4T, suppressed AA-induced bladder overactivity and significantly increased bladder capacity to 68.0 ± 31.3% at 1T (P < 0.05) and 98.5 ± 55.3% at 3-4T (P < 0.01) of the saline control capacity. MTEP dose dependently (0.1-50 mg kg(-1), i.v.) suppressed PNS inhibition of bladder overactivity at low intensity (1T) but not at high intensity (3-4T). During saline infusion PNS significantly (P < 0.05) increased bladder capacity to 167.7 ± 27.1% at 1T and 196.0 ± 37.4% at 3-4T. These inhibitory effects were not observed after MTEP (0.1-50 mg kg(-1), i.v.) which also increased bladder capacity. These results indicate that glutamic acid has a transmitter function in bladder and somato-bladder reflex mechanisms and raise the possibility that mGluR5 may be a target for pharmacological treatment of lower urinary tract disorders.

Squamous cell carcinoma of the renal pelvis with inferior vena cava and iliac vein tumor thrombus.

Renal cell carcinoma with inferior vena cava (IVC) tumor thrombus is a well described clinical entity. We report a case of 64-year-old man that developed an aggressive renal pelvic squamous cell carcinoma (SCC) with extensive IVC and bilateral iliac vein tumor thrombus. To our knowledge this is the fifth reported case of renal pelvic SCC with IVC tumor thrombus and the first involving the iliac veins. We review the current therapeutic options for treatment of SCC with IVC involvement.

Neuroblastoma impairs chemokine-mediated dendritic cell migration in vitro.

BACKGROUND/PURPOSE: Chemokine receptor (CCR7 [cysteine chemokine receptor 7]) and ligand (CCL19) interactions trigger dendritic cell (DC) recruitment from sites of antigen uptake to secondary lymphoid organs for T-cell priming and tumor lysis. Inhibition of this interaction may allow some aggressive tumors to evade immune detection. Although we have shown dysfunctional DC migration in murine neuroblastoma (NB) in vivo, the molecular mechanisms of impairment are unknown. We hypothesize that NB-induced aberrant CCR7-CCL19 signaling impairs DC migration. METHODS: Bone marrow-derived DCs were isolated from A/J mice (n = 24), matured, and cocultured with murine NB (TBJ) or media (control) for 7 days. CCR7 and CCL19 protein and RNA expressions by control and NB-exposed DC were measured by flow cytometry, Western blot analysis, and polymerase chain reaction. Migration assays using Transwell plates (Corning Incorporated, Corning, NY, via Fisher Scientific, Pittsburgh, Pa) were performed with matured DC and CCL19. Furthermore, to determine if these changes in DC migration could be overcome, superphysiological concentrations of CCL19 (100 ng/mL) were used. Results are reported as the average percentage +/- SD. RESULTS: No significant differences in CCR7 or CCL19 protein expression between tumor and control were seen at 7 days. However, NB significantly decreased CCL19-induced migration by more than 50%: control (26.48% +/- 1.52%) vs DC cocultured with TBJ (12.7% +/- 0.3%) (P < .05). Superphysiological doses up to 100 ng/mL CCL19 showed no significant upregulation in migration in DC cocultured with tumor cells. CONCLUSIONS: Although in vitro coculture with NB does not induce significant changes in either CCR7 or CCL19 expression, profound functional impairments in CCR7/CCL19-mediated migration occurs. These findings suggest that intracellular signal transduction pathways for these chemokines may be impaired by tumor. Targeting this chemokine-receptor pathway may provide a novel therapeutic strategy.

Murine neuroblastoma attenuates dendritic cell cysteine cysteine receptor 7 (CCR7) expression.

BACKGROUND/PURPOSE: Dendritic cell (DC) migration from tumors to T-cell priming sites is critical in developing antitumor cytotoxicity. Cysteine cysteine receptor 7 (CCR7), a promigratory chemokine receptor, regulates DC recruitment to secondary lymphoid organs. Tumors may inhibit CCR7 expression to evade immunodetection. Previous work implicates impaired DC migration as a critical defect in immunity to neuroblastoma (NB). However, the mechanism has yet to be defined. We hypothesize that NB abrogates DC CCR7 expression and signaling, leading to decreased antitumor immunity. METHODS: A/J mice (N = 36) were injected with saline (control) or murine NB (TBJ) and bone marrow-derived DC were isolated at 7, 14, and 28 days. CCR7 expression was analyzed by polymerase chain reaction, Western blot, and flow cytometry. Cytometry data were analyzed using the paired Student's t test. RESULTS: Dendritic cells isolated from mice with NB had a 60% increase in CCR7 protein expression by flow cytometry compared with control mice at day 7. However, there was a 43% downregulation of CCR7 expression by DC from tumor-bearing mice compared with controls 2 weeks postinoculation (P < .005). These observations were confirmed by polymerase chain reaction and Western blot analysis. CONCLUSION: Neuroblastoma initially upregulates CCR7 expression by DC. However, with tumor progression, this chemokine is downregulated, likely leading to impaired DC migration. Immunotherapeutic strategies to bypass or augment CCR7-dependent DC trafficking may improve survival for patients with aggressive disease.