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12/14/2012 Disclosures TRPV1 Mediates Anxious/Depressive No disclosures Behavior in a Murine Model of Chronic Abdominal Pain No conflict of interest NASPGHAN Annual Meeting Oct 20, 2012 John Rosen, MD Division of Pediatric

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  1. 12/14/2012 Disclosures TRPV1 Mediates Anxious/Depressive • No disclosures Behavior in a Murine Model of Chronic Abdominal Pain • No conflict of interest NASPGHAN Annual Meeting Oct 20, 2012 John Rosen, MD Division of Pediatric Gastroenterology, Hepatology, and Nutrition Ann & Robert H. Lurie Children’s Hospital of Chicago Northwestern University Feinberg School of Medicine 2 Introduction TRPV1 is distributed widely • Central and peripheral nervous system • Gastrointestinal and genitourinary visceral – Brain pain syndromes overlap – Spinal cord (especially lumbar) – DRG – C and A δ sensory fibers (largely lamina I&II) • Chronic GI and GU pain are associated – Cutaneous free nerve terminals with anxiety and depression • Intestinal mucosa / myenteric plexus • Mechanisms of chronic pain incompletely • Urothelium understood 3 4 Laboratory models suggest TRPV1 Hypothesis mediates allodynia • Lack of TRPV1 inhibits cyclophosphamide cystitis- induced increased mechanical sensitivity (Wang et al., Pain , 2008) TRPV1 mediates chronic pelvic allodynia • LPS sensitizes TRPV1 via activation of TLR4 in trigeminal sensory neurons in a murine model of infectious cystitis (Diogenes et al., J Dental Res , 2011) • LPS component of S Φ 874 bacteria induces TLR4 dependent chronic pelvic allodynia (Rudick et al., PLOS One , 2012) 5 6 1

  2. 12/14/2012 Methods Methods • 10-12 wk old female C57BL/6 mice • Transurethral infection with S Φ 874 300 S  874 – Capsazepine (TRPV1 antagonist) or vehicle Pain (% increase) 200 • Pelvic von Frey test of referred visceral pain NU14 S Φ 874 100 • Novelty suppressed feeding (NSF) behavioral test O18  wz * S  874+pDGal Source UTI Lab • Visceromotor response to bladder distension 0 Pain Acute Chronic 0 10 20 30 Time (days) 7 8 S Φ 874 induced chronic allodynia S Φ 874 induced chronic allodynia is abrogated by early capsazepine is abrogated by early capsazepine Post-infection Day 15 9 10 S Φ 874 induced chronic anxiety is Preliminary VMR Data blunted by early capsazepine Post-infection Day 15 11 12 2

  3. 12/14/2012 Summary Conclusions • S Φ 874 cystitis is associated with chronic • TRPV1 may mediate chronic allodynia and increased anxious/depressive behavior anxiety/depression induced by S Φ 874 bacterial cystitis • Capsazepine administered at the time of S Φ 874 infection abrogates chronic pelvic • Induction, but not maintenance, of allodynia allodynia and anxious/depressive behavior and anxiety/depression may be mediated by TRPV1 • Capsazepine administered 2 weeks after S Φ 874 infection does not alter allodynia or • NSF behavior testing can be a useful adjunct behavior in models of chronic abdominal/pelvic pain 13 14 Future Directions Acknowledgements • Other measures of visceral pain and behavior Northwestern University Medical College of Wisconsin Klumpp Laboratory Adrian Miranda, MD David Klumpp, PhD • Increased specificity of TRPV1 antagonist Anthony Schaeffer, MD University of Pittsburgh Medical Center Charles Rudick, PhD Gerald Gebhart, PhD Wenbin Yang, PhD Andrew Piotrowski, PhD • Additional bacterial and viral models Scholarship Committee Vladimir Pavlov, MD David Klumpp, PhD Lizzie Aguiniga – Human isolates Miguel Saps, MD Ryan Yaggie John Lavigne, PsyD – Acute and chronic pain Yelena Radulovic, MD, PhD Behavioral Phenotyping Core Mouse Histology Laboratory • Physiologic study of TRPV1 sensitization 15 16 Questions? 17 18 3

  4. 12/14/2012 S Φ 874 induced chronic allodynia is abrogated by early capsazepine 19 20 VMR data, add in TRPV1 background/methods if using this slide 21 22 Nature Reviews Drug Discovery 6, 357-372 (May 2007) 4

  5. 12/14/2012 Lack of TRPV1 inhibits cystitis-induced increased mechanical sensitivity in mice • Cyclophosphamide model of cystitis • B6 vs. TRPV -/- mice – Histologic evaluation of cystitis – Short-term urinary voiding frequency – Bladder capacity – Cystometry – Thermal and mechanical (VF) test of hindpaw 26 Wang, Bjorling, et al.. Pain. 2008; 139: 158-167. 27 28 Wang, Bjorling, et al.. Pain. 2008; 139: 158-167. Wang, Bjorling, et al.. Pain. 2008; 139: 158-167. Neonatal cystitis-induced colonic hypersensitivity in adult rats: a model of viscero-visceral convergence • Zymosan model of cystitis • Sprague-Dawley rats – Bladder and colon histology – NR1 expression in spinal cord (western blot) – In vivo pelvic nerve afferent fiber recording – Visceromotor response to colorectal distension 29 30 Miranda, Sengupta, et al.. Neurogastroenterology and Motility. 2011; 23: 683-e281. Miranda, Sengupta, et al.. Neurogastroenterology and Motility. 2011; 23: 683-e281. 5

  6. 12/14/2012 LPS Sensitizes TRPV1 via Activation of TLR4 in Murine Pelvic Pain Testing Trigeminal Sensory Neurons • Von Frey filaments • Cultured trigeminal neurons • Response to stimulus – Abdominal retraction • Sprague-Dawley rats – Licking or scratching – Immunofluorescence – Jumping – LPS binding assay • Specific to pelvic pain – Single cell calcium imaging – Hindpaw testing – iCGRP release assay – Weight – Patch-clamp electrophysiology 31 32 Diogenes, Hargreaves, et al.. J Dental Research. 2011; 90: 759-764. TRPV1 is increased in chronic Questions for me noninflammatory pain • Why capsazepine instead of RTX etc? • Peritoneum of women with chronic pelvic pain • Distribution of SQ cap—BBB? • Timing of SQ cap effect, metabolism? • Foci of endometriosis • VF pelvic testing for referred pain? Validated? • Irritable Bowel Syndrome (IBS) • Other behavioral tests? • TRPV1 central action, psych? • Need histology and urinary MPO to prove no • Inflammatory Bowel Disease + IBS change in acute inflammation? 33 34 6

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