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Attenuation of Cystitis and Pain Sensation in Mice Lacking Fatty Acid Amide Hydrolase

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Abstract

Endocannabinoids, such as N-arachidonoylethanolamine (AEA, also called anandamide), exert potent analgesic and anti-inflammatory effects. Fatty acid amide hydrolase (FAAH) is primarily responsible for degradation of AEA, and deletion of FAAH increases AEA content in various tissues. Since FAAH has been shown to be present in the bladder of various species, we compared bladder function, severity of experimental cystitis, and cystitis-associated referred hyperalgesia in male wild-type (WT) and FAAH knock-out (KO) mice. Basal concentrations of AEA were greater, and the severity of cyclophosphamide (CYP)-induced cystitis was reduced in bladders from FAAH KO compared to WT mice. Cystitis-associated increased peripheral sensitivity to mechanical stimuli and enhanced bladder activity (as reflected by increased voiding frequency) were attenuated in FAAH KO compared to WT mice. Further, abundances of mRNA for several pro-inflammatory compounds were increased in the bladder mucosa after CYP treatment of WT mice, and this increase was inhibited in FAAH KO mice. These data indicate that endogenous substrates of FAAH, including the cannabinoid AEA, play an inhibitory role in bladder inflammation and subsequent changes in pain perception. Therefore, FAAH could be a therapeutic target to treat clinical symptoms of painful inflammatory bladder diseases.

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References

  • Ahn K, Johnson DS, Mileni M, Beidler D, Long JZ, McKinney MK, Weerapana E, Sadagopan N, Liimatta M, Smith SE, Lazerwith S, Stiff C, Kamtekar S, Bhattacharya K, Zhang Y, Swaney S, Van Becelaere K, Stevens RC, Cravatt BF (2009) Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain. Chem Biol 16:411–420

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Aizawa N, Hedlund P, Füllhase C, Ito H, Homma Y, Igawa Y (2014) Inhibition of peripheral FAAH depresses activities of bladder mechanosensitive Nerve Fibers of the Rat. J Urol

  • Alvarez-Jaimes LJ, Palmer JA (2011) The role of endocannabinoids in pain modulation and the therapeutic potential of inhibiting their enzymatic degradation. Curr Pharm Biotechnol 12:1644–1659

    Article  CAS  PubMed  Google Scholar 

  • Anderson WB, Gould MJ, Torres RD, Mitchell VA, Vaughan CW (2014) Actions of the dual FAAH/MAGL inhibitor JZL195 in a murine inflammatory pain model. Neuropharmacology 81:224–230

    Article  CAS  PubMed  Google Scholar 

  • Birder L, Andersson KE (2013) Urothelial signaling. Physiol Rev 93:653–680

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Birder LA, Nakamura Y, Kiss S, Nealen ML, Barrick S, Kanai AJ, Wang E, Ruiz G, De Groat WC, Apodaca G, Watkins S, Caterina MJ (2002) Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1. Nat Neurosci 5:856–860

    Article  CAS  PubMed  Google Scholar 

  • Bisogno T, Maccarrone M (2013) Latest advances in the discovery of fatty acid amide hydrolase inhibitors. Expert Opin Drug Discov 8:509–522

    Article  CAS  PubMed  Google Scholar 

  • Bjorling DE, Jerde TJ, Zine MJ, Busser BW, Saban MR, Saban R (1999) Mast cells mediate the severity of experimental cystitis in mice. J Urol 162:231–236

  • Bjorling DE, Elkahwaji JE, Bushman W, Janda LM, Boldon K, Hopkins WJ, Wang ZY (2007) Acute acrolein-induced cystitis in mice. BJU Int 99:1523–1529

  • Bjorling DE, Wang ZY, Bushman W (2011) Models of inflammation of the lower urinary tract. Neurourol Urodyn 30:673–682

    Article  PubMed Central  PubMed  Google Scholar 

  • Blankman JL, Cravatt BF (2013) Chemical probes of endocannabinoid metabolism. Pharmacol 65:849–871

    Google Scholar 

  • Cencioni MT, Chiurchiù V, Catanzaro G, Borsellino G, Bernardi G, Battistini L, Maccarrone M (2010) Anandamide suppresses proliferation and cytokine release from primary human T-lymphocytes mainly via CB2 receptors. PLoS One 5:e8688

    Article  PubMed Central  PubMed  Google Scholar 

  • Cervero F, Laird JM (2004) Understanding the signaling and transmission of visceral nociceptive events. J Neurobiol 61:45–54

    Article  CAS  PubMed  Google Scholar 

  • Chang L, Luo L, Palmer JA, Sutton S, Wilson SJ, Barbier AJ, Breitenbucher JG, Chaplan SR, Webb M (2006) Inhibition of fatty acid amide hydrolase produces analgesia by multiple mechanisms. Br J Pharmacol 148:102–113

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Clapper JR, Moreno-Sanz G, Russo R, Guijarro A, Vacondio F, Duranti A, Tontini A, Sanchini S, Sciolino NR, Spradley JM, Hohmann AG, Calignano A, Mor M, Tarzia G, Piomelli D (2010) Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism. Nat Neurosci 13:1265–1270

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Conklin DJ, Haberzettl P, Lesgards JF, Prough RA, Srivastava S, Bhatnagar A (2009) Increased sensitivity of glutathione S-transferase Pnull mice to cyclophosphamide-induced urinary bladder toxicity. J Pharmacol Exp Ther 331:456–469

  • Cornelissen LL, Misajet B, Brooks DP, Hicks A (2008) Influence of genetic background and gender on bladder function in the mouse. Auton Neurosci 140:53–58

    Article  CAS  PubMed  Google Scholar 

  • Cravatt BF, Lichtman AH (2003) Fatty acid amide hydrolase: an emerging therapeutic target in the endocannabinoid system. Curr Opin Chem Biol 7:469–475

    Article  CAS  PubMed  Google Scholar 

  • Cravatt BF, Demarest K, Patricelli MP, Bracey MH, Giang DK, Martin BR, Lichtman AH (2001) Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci U S A 98:9371–9376

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • D’Argenio G, Valenti M, Scaglione G, Cosenza V, Sorrentini I, Di Marzo V (2006) Up-regulation of anandamide levels as an endogenous mechanism and a pharmacological strategy to limit colon inflammation. FASEB J 20:568–570

    PubMed  Google Scholar 

  • Daly DM, Collins VM, Chapple CR, Grundy D (2011) The afferent system and its role in lower urinary tract dysfunction. Curr Opin Urol 21:268–274

    Article  PubMed  Google Scholar 

  • Dinis P, Charrua A, Avelino A, Yaqoob M, Bevan S, Nagy I, Cruz F (2004) Anandamide-evoked activation of vanilloid receptor 1 contributes to the development of bladder hyperreflexia and nociceptive transmission to spinal dorsal horn neurons in cystitis. J Neurosci 24:11253–11263

    Article  CAS  PubMed  Google Scholar 

  • Füllhase C, Russo A, Castiglione F, Benigni F, Campeau L, Montorsi F, Gratzke C, Bettiga A, Stief C, Andersson KE, Hedlund P (2013) Spinal cord FAAH in normal micturition control and bladder overactivity in awake rats. J Urol 189:2364–2370

    Article  PubMed  Google Scholar 

  • Gandaglia G, Strittmatter F, La Croce G, Benigni F, Bettiga A, Castiglione F, Moschini M, Mistretta F, Gratzke C, Montorsi F, Stief C, Hedlund P (2013) The fatty acid amide hydrolase inhibitor oleoyl ethyl amide counteracts bladder overactivity in female rats. Neurourol Urodyn

  • Gonzalez EJ, Merrill L, Vizzard MA (2014) Bladder sensory physiology: neuroactive compounds and receptors, sensory transducers, and target-derived growth factors as targets to improve function. Am J Physiol Regul Integr Comp Physiol 306:R869–R878

    Article  CAS  PubMed  Google Scholar 

  • Gratzke C, Streng T, Park A, Christ G, Stief CG, Hedlund P, Andersson KE (2009) Distribution and function of cannabinoid receptors 1 and 2 in the rat, monkey and human bladder. J Urol 181:1939–1948

    Article  CAS  PubMed  Google Scholar 

  • Gratzke C, Streng T, Stief CG, Downs TR, Alroy I, Rosenbaum JS, Andersson KE, Hedlund P (2010) Effects of cannabinor, a novel selective cannabinoid 2 receptor agonist, on bladder function in normal rats. Eur Urol 57:1093–1100

    Article  PubMed  Google Scholar 

  • Hedlund P (2014) Cannabinoids and the endocannabinoid system in lower urinary tract function and dysfunction. Neurourol Urodyn 33:46–53

    Article  CAS  PubMed  Google Scholar 

  • Hill WG. Control of urinary drainage and voiding (2014) Clin J Am Soc Nephrol

  • Hillard CJ, Manna S, Greenberg MJ, DiCamelli R, Ross RA, Stevenson LA, Murphy V, Pertwee RG, Campbell WB (1999) Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1). J Pharmacol Exp Ther 289:1427–1433

    CAS  PubMed  Google Scholar 

  • Jayamanne A, Greenwood R, Mitchell VA, Aslan S, Piomelli D, Vaughan CW (2006) Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models. Br J Pharmacol 147:281–288

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Keay SK, Birder LA, Chai TC (2014) Evidence for bladder urothelial pathophysiology in functional bladder disorders. Biomed Res Int

  • Kinsey SG, Naidu PS, Cravatt BF, Dudley DT, Lichtman AH (2011) Fatty acid amide hydrolase blockade attenuates the development of collagen-induced arthritis and related thermal hyperalgesia in mice. Pharmacol Biochem Behav 99:718–725

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Klinger MB, Dattilio A, Vizzard MA (2007) Expression of cyclooxygenase-2 in urinary bladder in rats with cyclophosphamide-induced cystitis. Am J Physiol Regul Integr Comp Physiol 293:R677–R685

    Article  CAS  PubMed  Google Scholar 

  • Krishnan G, Chatterjee N (2012) Endocannabinoids alleviate proinflammatory conditions by modulating innate immune response in muller glia during inflammation. Glia 60:1629–1645

    Article  PubMed  Google Scholar 

  • Lichtman AH, Shelton CC, Advani T, Cravatt BF (2004) Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia. Pain 109:319–327

    Article  CAS  PubMed  Google Scholar 

  • Maione S, Costa B, Di Marzo V (2013) Endocannabinoids: a unique opportunity to develop multitarget analgesics. Pain 154:S87–S93

    Article  CAS  PubMed  Google Scholar 

  • Malley SE, Vizzard MA (2002) Changes in urinary bladder cytokine mRNA and protein after cyclophosphamide-induced cystitis. Physiol Genomics 9:5–13

    Article  CAS  PubMed  Google Scholar 

  • Massa F, Marsicano G, Hermann H, Cannich A, Monory K, Cravatt BF, Ferri GL, Sibaev A, Storr M, Lutz B (2004) The endogenous cannabinoid system protects against colonic inflammation. J Clin Invest 113:1202–1209

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Merriam FV, Wang ZY, Hillard CJ, Stuhr KL, Bjorling DE (2011) Inhibition of fatty acid amide hydrolase suppresses referred hyperalgesia induced by bladder inflammation. BJU Int 108:1145–1149

  • Merrill L, Malley S, Vizzard MA (2013) Repeated variate stress in male rats induces increased voiding frequency, somatic sensitivity, and urinary bladder nerve growth factor expression. Am J Physiol Regul Integr Comp Physiol 305:R147–56

  • Patel S, Rademacher DJ, Hillard CJ (2003) Differential regulation of the endocannabinoids anandamide and 2-arachidonylglycerol within the limbic forebrain by dopamine receptor activity. J Pharmacol Exp Ther 306:880–888

    Article  CAS  PubMed  Google Scholar 

  • Salaga M, Mokrowiecka A, Zakrzewski PK, Cygankiewicz A, Leishman E, Sobczak M, Zatorski H, Małecka-Panas E, Kordek R, Storr M, Krajewska WM, Bradshaw HB, Fichna J (2014)a Experimental colitis in mice is attenuated by changes in the levels of endocannabinoid metabolites induced by selective inhibition of fatty acid amide hydrolase (FAAH). J Crohns Colitis

  • Salaga M, Sobczak M, Fichna J (2014)b Inhibition of fatty acid amide hydrolase (FAAH) as a novel therapeutic strategy in the treatment of pain and inflammatory diseases in the gastrointestinal tract. Eur J Pharm Sci

  • Schlosburg JE, Kinsey SG, Lichtman AH (2009) Targeting fatty acid amide hydrolase (FAAH) to treat pain and inflammation. AAPS J 11:39–44

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Schrepf A, O’Donnell M, Luo Y, Bradley CS, Kreder K, Lutgendorf S (2014) Inflammation and inflammatory control in interstitial cystitis/bladder pain syndrome: associations with painful symptoms. Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. Pain

  • Selo-Ojeme DO, Onwude JL (2004) Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an ESSIC proposal. Interstitial cystitis. J Obstet Gynaecol 24:216–225

    Article  CAS  PubMed  Google Scholar 

  • Stanford EJ, Dell JR, Parsons CL (2007) The emerging presence of interstitial cystitis in gynecologic patients with chronic pelvic pain. Urology 69:53–59

    Article  PubMed  Google Scholar 

  • Storr MA, Keenan CM, Emmerdinger D, Zhang H, Yüce B, Sibaev A, Massa F, Buckley NE, Lutz B, Göke B, Brand S, Patel KD, Sharkey KA (2008) Targeting endocannabinoid degradation protects against experimental colitis in mice: involvement of CB1 and CB2 receptors. J Mol Med (Berl) 86:925–936

    Article  CAS  Google Scholar 

  • Storr MA, Keenan CM, Zhang H, Patel KD, Makriyannis A, Sharkey KA (2009) Activation of the cannabinoid 2 receptor (CB2) protects against experimental colitis. Inflamm Bowel Dis 15:1678–1685

    Article  PubMed  Google Scholar 

  • Strittmatter F, Gandaglia G, Benigni F, Bettiga A, Rigatti P, Montorsi F, Gratzke C, Stief C, Colciago G, Hedlund P (2012) Expression of fatty acid amide hydrolase (FAAH) in human, mouse, and rat urinary bladder and effects of FAAH inhibition on bladder function in awake rats. Eur Urol 61:98–106

    Article  CAS  PubMed  Google Scholar 

  • Tambaro S, Casu MA, Mastinu A, Lazzari P (2014) Evaluation of selective cannabinoid CB(1) and CB(2) receptor agonists in a mouse model of lipopolysaccharide-induced interstitial cystitis. Eur J Pharmacol

  • Tripp DA, Nickel JC, Wong J, Pontari M, Moldwin R, Mayer R, Carr LK, Doggweiler R, Yang CC, Mishra N, Nordling J (2012) Mapping of pain phenotypes in female patients with bladder pain syndrome/interstitial cystitis and controls. Eur Urol 62:1188–1194

  • Tyagi V, Philips BJ, Su R, Smaldone MC, Erickson VL, Chancellor MB, Yoshimura N, Tyagi P (2009) Differential expression of functional cannabinoid receptors in human bladder detrusor and urothelium. J Urol 181:1932–1938

    Article  CAS  PubMed  Google Scholar 

  • van de Merwe JP, Nordling J, Bouchelouche P, Bouchelouche K, Cervigni M, Daha LK, Elneil S, Fall M, Hohlbrugger G, Irwin P, Mortensen S, van Ophoven A, Osborne JL, Peeker R, Richter B, Riedl C, Sairanen J, Tinzl M, Wyndaele JJ (2008) Visceral pain is the most debilitating symptom of painful bladder syndrome. Eur Urol 53:60–67

    Article  PubMed  Google Scholar 

  • Walczak JS, Cervero F (2011) Local activation of cannabinoid CB1 receptors in the urinary bladder reduces the inflammation-induced sensitization of bladder afferents. Mol Pain 7:31

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wang ZY, Wang P, Merriam FV, Bjorling DE (2008) Lack of TRPV1 inhibits cystitis-induced increased mechanical sensitivity in mice. Pain 139:158–167

    Article  CAS  PubMed  Google Scholar 

  • Wang ZY, Wang P, Bjorling DE (2009) Role of mast cells and protease-activated receptor-2 in cyclooxygenase-2 expression in urothelial cells. Am J Physiol Regul Integr Comp Physiol 297:R1127–R1135

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wang ZY, Wang P, Bjorling DE (2013) Activation of cannabinoid receptor 2 inhibits experimental cystitis. Am J Physiol Regul Integr Comp Physiol 304:R846–R853

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wang ZY, Wang P, Bjorling DE (2014) Treatment with a cannabinoid receptor 2 agonist decreases severity of established cystitis. J Urol 191:1153–1158

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wise LE, Cannavacciulo R, Cravatt BF, Martin BF, Lichtman AH (2007) Evaluation of fatty acid amides in the carrageenan-induced paw edema model. Neuropharmacology 54:181–188

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This study was supported by NIH R01 DK 066349 (DEB).

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Surgical Sciences, University of Wisconsin, Madison, WI, USA

    Zun-Yi Wang, Peiqing Wang & Dale E. Bjorling

  2. Department of Pharmacology and Toxicology and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, USA

    Cecilia J. Hillard

  3. Department of Urology, University of Wisconsin, Madison, WI, USA

    Dale E. Bjorling

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  1. Zun-Yi Wang
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  2. Peiqing Wang
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  3. Cecilia J. Hillard
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  4. Dale E. Bjorling
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Correspondence to Zun-Yi Wang or Dale E. Bjorling.

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Wang, ZY., Wang, P., Hillard, C.J. et al. Attenuation of Cystitis and Pain Sensation in Mice Lacking Fatty Acid Amide Hydrolase. J Mol Neurosci 55, 968–976 (2015). https://doi.org/10.1007/s12031-014-0453-x

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  • DOI: https://doi.org/10.1007/s12031-014-0453-x

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