Abhijith Mally

Role of Opioid and Metabotropic Glutamate 5 Receptors in Pudendal Inhibition of Bladder Overactivity in Cats

PURPOSE We determined the role of opioid and metabotropic glutamate 5 receptors in the pudendal inhibition of bladder overactivity. MATERIALS AND METHODS Cystometrograms were performed in 11 cats under α-chloralose anesthesia by slowly infusing the bladder with saline or 0.25% acetic acid. Pudendal nerve stimulation at intensities of multiple times the threshold to induce observable anal twitching was applied during cystometrogram to inhibit the bladder overactivity induced by acetic acid irritation. Naloxone (0.1, 0.3 and 1 mg/kg intravenously) was administered to block opioid receptors, followed by MTEP (3 and 10 mg/kg intravenously) to block metabotropic glutamate 5 receptors. After each drug dose, pudendal inhibition of bladder overactivity was examined during cystometrogram. RESULTS Acetic acid irritated the bladder, induced bladder overactivity and significantly decreased mean ± SE bladder capacity to 23.6% ± 2.7% of saline control capacity. Pudendal nerve stimulation at 1 to 1.5 and 4 × threshold suppressed bladder overactivity and significantly increased mean capacity to 57.5% ± 8.1% (p = 0.0005) and 106% ± 15% (p = 0.0002), respectively, of saline control capacity. Naloxone had no effect on pudendal inhibition but MTEP eliminated the inhibition induced by low intensity stimulation and significantly decreased the inhibition induced by high intensity stimulation (p <0.05). Neither naloxone nor MTEP altered baseline bladder overactivity. CONCLUSIONS Opioid receptors are not involved in pudendal inhibition of bladder overactivity but metabotropic glutamate 5 receptors are partially involved. Understanding neurotransmitter mechanisms could improve the efficacy of neuromodulation therapy for overactive bladder and identify molecular targets for developing new drugs for overactive bladder.

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.

Contribution of opioid and metabotropic glutamate receptor mechanisms to inhibition of bladder overactivity by tibial nerve stimulation

The contribution of metabotropic glutamate receptors (mGluR) and opioid receptors to inhibition of bladder overactivity by tibial nerve stimulation (TNS) was investigated in cats under α-chloralose anesthesia using LY341495 (a group II mGluR antagonist) and naloxone (an opioid receptor antagonist). Slow infusion cystometry was used to measure the volume threshold (i.e., bladder capacity) for inducing a large bladder contraction. After measuring the bladder capacity during saline infusion, 0.25% acetic acid (AA) was infused to irritate the bladder, activate the nociceptive C-fiber bladder afferents, and induce bladder overactivity. AA significantly (P < 0.0001) reduced bladder capacity to 26.6 ± 4.7% of saline control capacity. TNS (5 Hz, 0.2 ms) at 2 and 4 times the threshold (T) intensity for inducing an observable toe movement significantly increased bladder capacity to 62.2 ± 8.3% at 2T (P < 0.01) and 80.8 ± 9.2% at 4T (P = 0.0001) of saline control capacity. LY341495 (0.1-5 mg/kg iv) did not change bladder overactivity, but completely suppressed the inhibition induced by TNS at a low stimulus intensity (2T) and partially suppressed the inhibition at high intensity (4T). Following administration of LY341495, naloxone (0.01 mg/kg iv) completely eliminated the high-intensity TNS-induced inhibition. However, without LY341495 treatment a 10 times higher dose (0.1 mg/kg) of naloxone was required to completely block TNS inhibition. These results indicate that interactions between group II mGluR and opioid receptor mechanisms contribute to TNS inhibition of AA-induced bladder overactivity. Understanding neurotransmitter mechanisms underlying TNS inhibition of bladder overactivity is important for the development of new treatments for bladder disorders.

Combination of Foot Stimulation and Tramadol Treatment Reverses Irritation Induced Bladder Overactivity in Cats

PURPOSE We determined whether transcutaneous electrical foot stimulation combined with a low dose of tramadol (Sigma-Aldrich®) could completely suppress bladder overactivity. MATERIALS AND METHODS Repeat cystometrograms were performed in 18 α-chloralose anesthetized cats by infusing the bladder with saline or 0.25% acetic acid. Transcutaneous electrical stimulation (5 Hz) of the cat hind foot at 2 to 4 times the threshold intensity needed to induce observable toe movement was applied to suppress acetic acid induced bladder overactivity. Tramadol (1 to 3 mg/kg intravenously) was administered to enhance foot inhibition. RESULTS Acetic acid irritated the bladder, induced bladder overactivity and significantly decreased bladder capacity to a mean ± SE of 26% ± 5% of saline control capacity (p <0.01). Without tramadol, foot stimulation at 2 and 4 threshold intensity applied during acetic acid cystometrograms significantly increased bladder capacity to a mean of 47% ± 5% and 62% ± 6% of saline control capacity, respectively (p <0.05). Without foot stimulation, tramadol (1 mg/kg) only slightly changed bladder capacity to a mean of 39% ± 2% of saline control capacity (p >0.05), while 3 mg/kg significantly increased capacity to 85% ± 14% that of control (p <0.05). However, 1 mg/kg tramadol combined with foot stimulation increased bladder capacity to a mean of 71% ± 18% (2 threshold intensity) and 84% ± 14% (4 threshold intensity), respectively, which did not significantly differ from saline control capacity. In addition, long lasting (greater than 1.5 to 2 hours) post-stimulation inhibition was induced by foot stimulation combined with 3 mg/kg tramadol treatment. CONCLUSIONS This study suggests a new treatment strategy for overactive bladder by combining foot stimulation with a low dose of tramadol, which is noninvasive and has potentially high efficacy and fewer adverse effects.

Effect of methysergide on pudendal inhibition of micturition reflex in cats

The role of 5-HT2 and opioid receptors in pudendal inhibition of bladder activity induced by intravesical infusion of saline or 0.25% acetic acid (AA) was investigated in anesthetized cats using methysergide (a 5-HT2 receptor antagonist) and naloxone (an opioid receptor antagonist). AA irritated the bladder and significantly (P<0.0001) reduced bladder capacity to 27.0 ± 7.4% of saline control capacity. Pudendal nerve stimulation (PNS) at multiples of the threshold (T) intensity for inducing anal sphincter twitching restored bladder capacity to 60.1 ± 8.0% at 1-2T (P<0.0001) and 92.2 ± 14.1% at 3-4T (P=0.001) of the saline control capacity. Methysergide (0.03-1mg/kg, i.v.) suppressed low intensity (1-2T) PNS inhibition but not high intensity (3-4T) inhibition, and also significantly (P<0.05) increased control bladder capacity at the dosage of 0.3-1mg/kg. During saline infusion without AA irritation, PNS significantly increased bladder capacity to 150.8 ± 9.9% at 1-2T (P<0.01) and 180.4 ± 16.6% at 3-4T (P<0.01) of the saline control capacity. Methysergide (0.1-1 mg/kg) significantly (P<0.05) increased saline control bladder capacity and suppressed PNS inhibition at the dosage of 0.03-1mg/kg. After methysergide treatment (1 mg/kg), naloxone significantly (P<0.05) reduced control bladder capacity during AA infusion but had no effect during saline infusion. Naloxone also had no influence on PNS inhibition. These results suggest that 5-HT2 receptors play a role in PNS inhibition of reflex bladder activity and interact with opioid mechanisms in micturition reflex pathway. Understanding neurotransmitter mechanisms underlying pudendal neuromodulation is important for the development of new treatments for bladder disorders.

Inhibition of micturition reflex by activation of somatic afferents in posterior femoral cutaneous nerve

•  Activation of afferents in the posterior femoral cutaneous nerve (PFCN) can reflexively induce efferent firing in the pudendal nerve and pudendal afferent firing via a motor–sensory coupling. •  Activation of pudendal afferent nerves can inhibit the micturition reflex, suggesting PFCN stimulation might also inhibit the micturition reflex. •  This study discovered a somato‐bladder inhibitory reflex elicited by electrical or tactile stimulation of cutaneous afferents in the PFCN, but excluded the involvement of pudendal nerves. •  This PFCN‐bladder inhibitory reflex could be utilized to develop new neuromodulation therapies for lower urinary tract disorders.

273 INVOLVEMENT OF 5-HT2 RECEPTOR IN PUDENDAL NERVE INHIBITION OF NOCICEPTIVE AND NON-NOCICEPTIVE BLADDER ACTIVITY IN CATS

INTRODUCTION AND OBJECTIVES: The goal of this video is to present a streamlined approach to laparoscopic abdominal sacralcolpopexy. In light of the FDA warnings regarding transvaginal mesh placement and the withdrawal of transvaginal mesh kits from the marketplace, patients are seeking alternative minimally invasive options to address vaginal prolapse. The open abdominal sacralcolpopexy technique has stood the test of time and consistently delivers 95% success rates with tolerable complication rates and specifically, very low mesh complication rates. Translating the open approach to the laparoscopic approach has been made possible with modern technology. METHODS: A compendium of cases by one surgeon is presented in video format to illustrate the main technical points of the procedure. These include: port placement, dissection planes, mesh attachment to vaginal vault and to sacral promontory, and mesh coverage. A novel new vaginal manipulator specifically designed for this procedure will also be shown. RESULTS: Use of a novel new vaginal manipulator facilitates dissection of the vaginal vault and makes it easier to perform intracorporal laprascopic suturing without the need for expensive robotic technology. CONCLUSIONS: Laparoscopic abdominal sacral colpopexy is feasible and safe and can be performed within a reasonable time frame with few complications, by surgeons who are comfortable with other laparoscopic procedures.

Ureteral Ectopia Inserting into Ipsilateral Epididymis Resulting in Inflammatory Paratesticular Tumor

An 8-year-old male with a history of VACTERL association was found to have a paratesticular mass. The patient was treated successfully with a radical orchiectomy and found to have ureteral ectopia inserting into the ipsilateral epididymis, resulting in this paratesticular mass caused by inflammation of the epididymis. This is the only reported case in the English literature of an ectopic ureter inserting into the epididymis and presenting as a paratesticular tumor. In unclear cases of paratesticular, inflammatory appearing masses, inguinal exploration is warranted.