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Neurotransmitter Mechanisms Underlying Neuromodulation of Bladder Overactivity

Neurotransmitter Mechanisms Underlying Neuromodulation of Bladder Overactivity. Changfeng Tai, Ph.D. Assistant Professor. Department of Urology University of Pittsburgh. Overactive Bladder - OAB. A syndrome characterized by urgency with or without

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Neurotransmitter Mechanisms Underlying Neuromodulation of Bladder Overactivity

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  1. Neurotransmitter Mechanisms Underlying Neuromodulation of Bladder Overactivity Changfeng Tai, Ph.D. Assistant Professor Department of Urology University of Pittsburgh

  2. Overactive Bladder - OAB • A syndrome characterized by urgency with or without urge incontinence, usually with frequency and nocturia • About 33.3 million adults suffer from OAB in US • Pathology and etiology - unknown • First-line pharmacotherapy - antimuscarinic drugs (tolterodine, or oxybutynin, etc.) • Low efficacy with side effects - dry mouth, constipation, headache, and blurred vision • An effective treatment is needed – high efficacy, less side effects, non-invasive • Currently neuromodulation is only used after the pharmacotherapy is failed. • Sacral neuromodulation and tibial neuromodulation – FDA approved for OAB

  3. Sacral Neuromodulation • Invasive – need surgery to implant a stimulator • Cost – more than $20K for surgery and stimulator • Efficacy – about 60-80% implanted patients have more than 50% improvement for 5-10 years • Acceptability – only 40,000 implantation worldwide, but 33.3 million adults suffer from OAB in United States • Limitation – mainly due to its invasiveness Kessler TM and Fowler CJ (2008) Nat Clin Pract Urol doi:10.1038/ncpuro1251

  4. Tibial Neuromodulation Needle Electrode Clinical Setting Ruiz et al (2004)European Urology • Minimally invasive – needle insertion • Frequent clinic visit – 30 minutes/week for 12 weeks, then once per 2-3 weeks • Low efficacy – about same as antimuscarinic drugs

  5. Our Hypothesis • Neuromodulation activates a specific group of afferent nerves to deliver neurotransmitters in the CNS to modulate the bladder activity • Efficacy of neuromodulation therapy can be increased by enhancing the neurotransmitter mechanisms involved Our Goal • Identify the neurotransmitters and receptors involved in neuromodulation therapies • Develop new, non-invasive, effective neuromodulation therapies

  6. Images from "Anatomy of the Human Body" by Henry Gray Sacral Neuromodulation (Sacral S3 Root) Sacral (S3) Tibial Nerve Pudendal Nerve

  7. = Excitatory synapse = Inhibitory synapse = Neuron Micturition Reflex Pathways and Animal Model Brain/PAG/PMC A-fiber PudN = Pudendal nerve TibialN = Tibial Nerve PMC = Pontine micturition center PAG = Periaqueductal grey 2 1 C-fiber 3 1 1 = Inhibitory interneuron 2 = Spinal tract neuron 3 = Excitatory interneuron 4 = Parasympathetic preganglionic Neuron Spinal Cord 4 PudN / TibialN Bladder • A-fiber --- bladder distention using saline • C-fiber --- 0.25% acetic acid • Animal model – anesthetized cats

  8. Neurotransmitters Involved in Pudendal Neuromodulation

  9. 60 cmH2O 100 sec Pudendal Neuromodulation – Acetic Acid Irritation Start Infusion Saline Stop Infusion AA Stop Infusion AA Stop Infusion 1 T AA Stop Infusion 4 T Jeffrey Larson, P. Dafe Oagagan, et al. (2011)Journal of Physiology

  10. 60 cmH2O 100 sec Pudendal Neuromodulation – mGluR5 Receptor MTEP – Metabotropic glutamate receptor 5 (mGluR5) antagonist MTEP (i.v.) 0.1 mg/kg 1 T 4 T 0.3 mg/kg 4 T 1 T 1 mg/kg 1 T 4 T 3 mg/kg 4 T 1 T 10 mg/kg 4 T 1 T 30 mg/kg 4 T 1 T 50 mg/kg 4 T 1 T Jeffrey Larson, P. Dafe Oagagan, et al. (2011)Journal of Physiology

  11. Pudendal Neuromodulation – mGluR5 Receptor # # # * * * * * Jeffrey Larson, P. Dafe Oagagan, et al. (2011)Journal of Physiology

  12. 50 cmH2O B. 1T A. AA Control C. 4T 200 sec # * # # Start Infusion Start Infusion Start Infusion * # * * Before Naloxone * * * * 0.1 mg/kg Naloxone Stop Infusion 0.3 mg/kg Naloxone 1.0 mg/kg Naloxone Pudendal Neuromodulation – Opioid Receptor Naloxone – opioid receptor antagonist Abhijith D. Mally, et al. (2013 in press)Journal of Urology

  13. Pudendal Neuromodulation – Serotonin 5HT2 Receptor # * # # * * * * * # * * Methysergide – Serotonin 5HT2 receptor antagonist FDA approved for treatment of headaches

  14. Pudendal Neuromodulation – Serotonin 5HT3 Receptor Ondansetron – Serotonin 5HT3 receptor antagonist FDA approved for treatment of nausea and vomiting

  15. Pudendal Neuromodulation – Multiple Neurotransmitters Not involved: Opioid receptor Partially involved: Metabotropic glutamate receptor 5 Serotonin 5HT2 or 5HT3 receptor A single major neurotransmitter or multiple neurotransmitters?

  16. Neurotransmitters Involved in Tibial Neuromodulation

  17. Start Infusion 75 cmH2O 200 sec Stop Infusion Stop Infusion Stop Infusion Stop Infusion Tibial Neuromodulation – Acetic Acid Irritation A Saline AA AA 4T B * AA Stop Infusion 8T * * AA Changfeng Tai, et al. (2012)American Journal of Physiology - Renal Physiology

  18. 50 cmH2O 200 sec Tibial Neuromodulation – Opioid Receptor A. AA Control B. 4T C. 8T No Naloxone 0.001 mg/kg Naloxone 0.01 mg/kg Naloxone 0.1 mg/kg Naloxone 1.0 mg/kg Naloxone Changfeng Tai, et al. (2012)American Journal of Physiology - Renal Physiology

  19. Start Infusion 50 cmH2O 200 sec Stop Infusion Stop Infusion Stop Infusion Stop Infusion Tibial Neuromodulation – Opioid Receptor AA Control * * * 8T * # # 16T AA Control Changfeng Tai, et al. (2012)American Journal of Physiology - Renal Physiology

  20. 100 cmH2O • Before Stimulation B. 2T C. 4T 500 sec Start Infusion Start Infusion Start Infusion Stop Infusion Tramadol0 mg/kg Tramadol0.3 mg/kg Tramadol1 mg/kg Tramadol3 mg/kg Tramadol7 mg/kg Tibial Neuromodulation – Tramadol Enhancement Tramadol – opioid receptor agonist Fan Zhang, et al. (2012)American Journal of Physiology - Renal Physiology

  21. Tibial Neuromodulation – Tramadol Enhancement Tramadol side effects: nausea, vomiting, dizziness, constipation Fan Zhang, et al. (2012)American Journal of Physiology - Renal Physiology

  22. B A Start Infusion before stimulation 100 cmH2O 500 sec 2T C 4T after stimulation Stop Infusion Tibial Neuromodulation – Tramadol and Post-Stimulation Inhibition Tramadol 3 mg/kg Fan Zhang, et al. (2012)American Journal of Physiology - Renal Physiology

  23. 100 cmH2O A. After 7 mg/kg Tramadol 250 sec Start Infusion control B. Post-stimulation Capacity Increase control 2T Stop Infusion 4T 1st 2nd 3rd 4th 5th Tibial Neuromodulation – Tramadol and Post-Stimulation Inhibition Fan Zhang, et al. (2012)American Journal of Physiology - Renal Physiology

  24. A. AA control B. 2T C. 4T Start infusion Before LY341495 0.1 mg/kg LY341495 0.3 mg/kg LY341495 1 mg/kg LY341495 3 mg/kg LY341495 5 mg/kg LY341495 Stop infusion Tibial Neuromodulation – mGluR2/3 receptor LY341495 – metabotropic glutamate receptor2/3 (mGluR2/3) antagonist 75 cmH2O 100 sec

  25. * * * * * * * * * # # # # # Tibial Neuromodulation – mGluR2/3 receptor

  26. * * * * * # # Tibial Neuromodulation – Synergetic Interaction between mGluR2/3 and Opioid Receptors A. LY341495 pretreated B. No LY341495 AA control 4T AA control 4T Start infusion Start infusion Start infusion Start infusion Reduce Tramadol Dosage? Before Naloxone Before Naloxone C. Summary 0.001 mg/kg Naloxone 0.001 mg/kg Naloxone 0.01 mg/kg Naloxone 0.01 mg/kg Naloxone Stop infusion Stop infusion 75 cmH2O 0.1 mg/kg Naloxone 100 sec 1 mg/kg Naloxone Stop infusion Stop infusion

  27. Neurotransmitters Involved in Foot Neuromodulation

  28. Foot – Tibial Nerve Human Animal - Cat Tibial Nerve Hindlimb Ankle Electrode #2 Electrode #1

  29. Start Infusion * * Control Stop 20 Hz Stop 20 cmH2O 100 sec Control Stop Stop 5 Hz Control Stop Foot – Saline infusion Changfeng Tai, et al. (2010)BJU International

  30. A. Control B. Post-Stimulation Effect Start Infusion Start Infusion Initial CMG Initial CMG Isovolumetric contractions for 30 minutes 5Hz stimulation for 30 minutes 1st 1st 2nd 2nd 3rd 3rd 200cmH2O 200cmH2O 200sec 200sec 4th 4th 5th 5th Isovolumetric contractions for 30 minutes 5Hz stimulation for 30 minutes 6th 6th 7th 7th 8th 8th 9th 9th 10th 10th Stop Infusion Stop Infusion Foot – Post-stimulation Effect (Saline) Guoqing Chen, et al. (2012)Journal of Urology

  31. * after 1st 30 min after 2nd 30 min Foot – Post-stimulation Effect (Saline) Guoqing Chen, et al. (2012)Journal of Urology

  32. Start Infusion Saline Control Stop * 0.25% AA Stop * * 0.25% AA 40 cmH2O Stop 100 sec 5 Hz 0.25% AA Stop 0.25% AA Stop 20 Hz 0.25% AA Stop Foot – Acetic Acid Infusion Changfeng Tai, et al. (2010)BJU International No post-stimulation Effect

  33. * * * 50 cm H2O 100 sec Foot – Opioid Receptor Start Infusion Saline Stop Infusion 0.25% AA Stop Infusion 0.25% AA Stop Infusion 4 T Naloxone 1 mg/kg 0.25% AA Stop Infusion 0.25% AA Stop Infusion 4 T 0.25% AA Stop Infusion 8 T Changfeng Tai, et al. (2012)Journal of Urology

  34. A. Tramadol alone C. Summary Start Infusion @ * Before Tramadol * Stop Infusion Tramadol 1 mg/kg @ * # # Tramadol 3 mg/kg # # B. Tramadol + Stimulation Before Tramadol 2T 4T 50 cmH2O 50 cmH2O Tramadol 1 mg/kg 100 sec 100 sec 2T 4T Tramadol 3 mg/kg 2T 4T Foot – Tramadol Enhancement Abhijith D. Mally, et al. (2012)Journal of Urology

  35. A After 3 mg/kg Tramadol Start Infusion Pre- Stimulation Stop Infusion 2T 4T Post- Stimulation Stop Infusion Increased Capacity B * 50 cmH2O 100 sec # # # C Foot – Tramadol and Post-stimulation Effect Abhijith D. Mally, et al. (2012)Journal of Urology

  36. Start Infusion A. After 3 mg/kg Tramadol control 75 cmH2O control 100 sec 2 T Stop Infusion 4 T 1st 2nd 3rd 4th 5th B. Post-stimulation Capacity Increase Foot – Tramadol and Post-stimulation Effect Abhijith D. Mally, et al. (2012)Journal of Urology

  37. * Foot – Application to Human Subject Skin Surface Electrodes Stimulation: 1.5 hour duration, 5 Hz, 0.2 ms, 2-3T Drinking water: 1000 ml during 1.5 hour stimulation N = 4 subjects

  38. Foot – A Shoe Stimulator for OAB Non-invasive No frequent clinic visit No adverse effect High efficacy – continuous stimulation Embedded in the shoe Combining with Tramadol Treatment?

  39. Acknowledgement Department of Pharmacology & Chemical Biology University of Pittsburgh Xianchun Wang, M.D. Timothy Ungerer, B.S. James R. Roppolo, Ph.D. William C. de Groat, Ph.D. Department of Urology University of Pittsburgh Bing Shen, D.V.M. Jicheng Wang, Ph.D. Hailong Liu, Ph.D. Mang Chen, M.D. Jeffery Larson, M.D. P. Dafe Ogagan, M.D. Abhijith Dev Mally, M.D. Fan Zhang, M.D. Guoqing Chen, M.D. Shouguo Zhao, Ph.D. Shaohua Huang, Ph.D. Yosuke Matsuta, M.D., Ph.D. Zeyad Schwen, B.S. National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) Department of Defense (DOD) Christopher and Dana Reeve Foundation

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