Etiology

• Colon-Bladder Cross-sensitization Takes Place in Periphery
  Brumovsky PR, Feng B, Xu L, McCarthy CJ, Gebhart GF. Cystitis increases colorectal afferent sensitivity in the mouse. Am J Physiol Gastrointest Liver Physiol. 2009 Oct 1. [Epub ahead of print]
  In these animal studies, researchers found that irritation of the bladder increased the sensitivity of colon and rectal afferent (sensing) nerves to mechanical stimulation (such as stretching) and increased the proportion of colon and rectal afferents that sensitive to chemical changes. The study supports the idea that cross-sensitization taking place between the organs themselves contributes to the phenomenon.

• IC Patients May Not Get Used to Certain Sensations
  Lowenstein L, Kenton K, Mueller ER, Brubaker L, Heneghan M, Senka J, Fitzgerald MP. Patients with painful bladder syndrome have altered response to thermal stimuli and catastrophic reaction to painful experiences. Neurourol Urodyn. 2009;28(5):400-4.
  IC patients’ nerves may not be more sensitive to bothersome sensations, but patients may not be able to get used to the sensations. Researchers tested 11 patients’ and 10 controls’ sensation of warmth in the areas above the pubis (over the bladder), which is served by nerves from the T12 level of the spinal cord, and on the buttocks surrounding the anal area, which is served by nerves from the S3 level of the spinal cord. Patients were actually less sensitive to warmth in the T12 area than controls, but had the same level of sensation on other parts of their body. Controls got used to the warmth in these two areas faster than the patients. Patients’ score on a pain “catastrophizing” (helplessness and hopelessness) scale were higher for those who had worse symptoms, those who had had symptoms for a longer time, and those who needed higher temperatures above the bladder to feel the sensation.

• Review Shows Overlap Between IC and Other Conditions
  Rodríguez MA, Afari N, Buchwald DS; National Institute of Diabetes and Digestive and Kidney Diseases Working Group on Urological Chronic Pelvic Pain. Evidence for Overlap Between Urological and Nonurological Unexplained Clinical Conditions. J Urol. 2009 Sep 14. [Epub ahead of print]
  Medical literature details considerable overlap between IC and many other conditions, especially irritable bowel syndrome (IBS). Estimates of the overlap with IBS range up to 79 percent. Overlap was difficult to estimate, said the authors, because definitions varied. The group called for standardized definitions and rigorously designed, well-controlled studies to assess the overlap and look at what the common mechanisms might be.

• Uncontrolled Study Suggests Role of Nanobacteria
  Zhang QH, Shen XC, Zhou ZS, Chen ZW, Lu GS, Song B. Decreased nanobacteria levels and symptoms of nanobacteria-associated interstitial cystitis/painful bladder syndrome after tetracycline treatment. Int Urogynecol J Pelvic Floor Dysfunct. 2009 Sep 17. [Epub ahead of print]
  These Chinese researchers said they grew microbes “similar to nanobacteria” from IC bladder tissue. In addition, a genetic study suggested that nanobacteria might be the disease-causing organisms. In 11 patients, tetracycline treatment reduced levels of the nanobacteria and eased symptoms. These researchers concluded that nanobacteria may cause some cases of IC/painful bladder syndrome (PBS). This study did not have a healthy control group for comparison, however.

• Lack of Estrogen May Increase Pain Sensitivity
  Sanoja R, Cervero F. Estrogen-dependent changes in visceral afferent sensitivity. Auton Neurosci. 2009 Jul 22. [Epub ahead of print]
  There has been debate in medicine over the role of estrogen in chronic pain, with some suggesting that estrogen increases pain sensitivity, But these anesthesiologists say no.  In their experience, permanent reductions in estrogen levels, such as when ovaries are removed, actually brings on hyperalgesia, that is, hypersensitivity to pain.  The type of hyperalgesia that they often see in patients without estrogen is sensitivity to touch or pressure and to temperature in the abdominal and pelvic regions as well as sensitivity of the internal organs themselves.  The phenomenon has a slow onset, and it lasts a long time, but it can be prevented or reversed when patients take estrogen, said the authors.  They discussed the possible role of estrogen in preventing chronic painful states.

• Abdominal Myofascial Pain Can Contribute to Chronic Pelvic Pain
  Montenegro ML, Gomide LB, Mateus-Vasconcelos EL, Rosa-E-Silva JC, Candido-Dos-Reis FJ, Nogueira AA, Poli-Neto OB. Abdominal myofascial pain syndrome must be considered in the differential diagnosis of chronic pelvic pain. Eur J Obstet Gynecol Reprod Biol. 2009 Jul 21. [Epub ahead of print]
  Abdominal myofascial pain syndrome often accompanies chronic pelvic pain in women and needs to be diagnosed early so unnecessary investigations can be avoided, argue these gynecologists.  They said that evidence points to the musculoskeletal system being compromised in some way in most women with chronic pelvic pain and that in 15 percent of these cases, chronic pelvic pain and abdominal myofascial pain syndrome go hand in hand.

• Trigger Points Overlap with Acupuncture Points
  Dorsher PT. Myofascial Referred-Pain Data Provide Physiologic Evidence of Acupuncture Meridians. J Pain. 2009 Apr 29. [Epub ahead of print]
  Pain from internal organs, such as the bladder, refers to very specific trigger points in muscles and tissues of the outer body.  Those trigger points correspond well to anatomically related acupuncture points, lending some physiologic credibility to acupuncture points.  This physical medicine specialist superimposed referred pain patterns for different subsets of trigger points onto a virtual human model along with the acupuncture points related to specific organs.  (Traditional acupuncture points are along meridians that correspond to 12 organs.)  For all 12 subsets of trigger point regions, their referred pain patterns predicted the distribution of the corresponding acupuncture meridians, especially in the extremities.  Interestingly, a bladder acupoint (BL-28) at the level of the second segment of the sacrum (S2) appears to “regulate the bladder” and “facilitate urination.”  Physicians typically implant the InterStim neuromodulation device to stimulate the S2 nerve root.  That “provides a contemporary example of allopathic medicine’s rediscovery of the clinical findings of the acupuncture tradition,” said the author.

• IL-8 Could Be Key to IC
  Tseng-Rogenski S, Liebert M. Interleukin 8 is essential for normal urothelial cell survival. Am J Physiol Renal Physiol. 2009 Jun 17. [Epub ahead of print]
  The immune system chemical interleukin 8 (IL-8, CXCL8) is essential for the survival of normal urinary tract lining (urothelial) cells, and the levels are low in IC patients.  These findings may be important keys to the cause of IC.  These researchers discovered this through a number of experiments.  They found that supplementing cultures of normal urothelial cells with IL-8 promoted cell growth.  Inhibiting IL-8 expression with a small piece of RNA caused normal urothelial cells to die.  Adding IL-8 back, however, rescued them.  That rescue process, in turn, could be blocked by antibodies to one of the receptors for IL-8.  IC patients have low levels of mRNA for IL-8, the genetic messenger that helps assemble this protein.

• Early Bladder Inflammation Linked to Adult Bladder Hypersensitivity in Rats
  Randich A, Mebane H, Ness TJ. Ice water testing reveals hypersensitivity in adult rats that experienced neonatal bladder inflammation: implications for painful bladder syndrome/interstitial cystitis. J Urol. 2009 Jul;182(1):337-42. Epub 2009 May 17.
  Rats that had bladder inflammation shortly after birth had hypersensitive bladders (to cold) as adults.  That was not true of rats whose bladders weren’t inflamed, found these researchers.  In addition, it did not take re-inflammation in adulthood for this hypersensitivity to be present.  The effects of inflammation shortly after birth did not relate to hormonal cycles.

• Females Have More Bladder Sensors for Pain from Acid
  Kobayashi H, Yoshiyama M, Zakoji H, Takeda M, Araki I. Sex differences in the expression profile of acid-sensing ion channels in the mouse urinary bladder: a possible involvement in irritative bladder symptoms. BJU Int. 2009 Jun 2. [Epub ahead of print]
  Acid-sensitive ion channels (ASICs), which are thought to play an important role in pain perception, are abundant in the bladder and are expressed much more in female than in male mice.  Although the expression of a vanilloid receptor (the type that responds to hot pepper-like substances) was also different in males and females, the researchers found that it was not as abundantly expressed as ASICs.  ASICs may be involved in the different response of the sexes to acid irritation in the bladder.

• Immune System, Inflammatory Genes Revved Up in IC
  Gamper M, Viereck V, Geissbuehler V, Eberhard J, Binder J, Moll C, Rehrauer H, Moser R. Gene expression profile of bladder tissue of patients with ulcerative interstitial cystitis. BMC Genomics. 2009 Apr 28;10(1):199. [Epub ahead of print]
  IC patients with Hunner’s ulcers have some 1,000 genes that are more active than in healthy people -- in patterns that are similar to those of people with immune system, lymphatic, and autoimmune disease.  These Swiss researchers looked at what genes were expressed in tissue from the bladders of IC patients who have Hunner’s ulcers.  The gene chips detected some 3,500 signals that were different between IC patients and healthy people, including about 2,000 that were expressed more than twice as much, which correlates to some 1,000 genes.  They noted those patterns and also said that the dominant biological processes represented were immune and inflammatory responses.  Many of the up-regulated genes were expressed in white blood cells, suggesting that invasion of these cells into the bladder wall is a dominant feature of IC with Hunner’s ulcers.  Looking at the gene expression picture in IC patients who don’t have Hunner’s ulcers will help show whether these gene expression differences could help diagnose IC.

• Polyoma Virus May Cause Some IC
  Eisen DP, Fraser IR, Sung LM, Finlay M, Bowden S, O’Connell H. Decreased viral load and symptoms of polyomavirus-associated chronic interstitial cystitis after intravesical cidofovir treatment. Clin Infect Dis. 2009 May 1;48(9):e86-8.
  In this case report from a hospital in Australia, the urologists describe a patient who had high levels of a polyomavirus in the urine.  After the urologists began treatment with an instillation of cidofovir (an anti-viral medicine), virus levels decreased dramatically, and the patient got much better.  Another patient with milder symptoms had the virus in their urine intermittently.  Polyomaviruses, particularly BK virus, may cause some cases of IC, the authors concluded.

• Blood Vessel Growth Factor May Play Role in Pinpoint Bleeding, Pain
  Kiuchi H, Tsujimura A, Takao T, Yamamoto K, Nakayama J, Miyagawa Y, Nonomura N, Takeyama M, Okuyama A. Increased vascular endothelial growth factor expression in patients with bladder pain syndrome/interstitial cystitis: its association with pain severity and glomerulations. BJU Int. 2009 Mar 4. [Epub ahead of print]
  Vascular endothelial growth factor (VEGF) can prompt the growth of blood vessels that are abnormal.  The vessels are immature and don’t have the normal coverage of pericytes, which are a type of smooth muscle cell that surrounds the outside of blood vessels.  When there aren’t enough of these cells covering blood vessels, they leak.  To find out whether VEGF plays a role in the glomerulations in IC patients’ bladders, these researchers took tissue specimens from the bladders of 30 IC patients with glomerulations (pinpoint bleeding) and 10 controls without glomerulations and looked at the tissue for expression of VEGF, the density of small blood vessels, and the proportion of immature blood vessels, which aren’t sufficiently covered by pericytes.  IC patients had significantly higher expression of VEGF than controls.  In addition, patients with worse pain had significantly more VEGF than patients with mild pain.  IC patients also had a higher proportion of immature vessels than controls, although the density of small vessels was not significantly different from the density in controls.  VEGF may contribute to pain and promote the formation of immature vessels in IC patients’ bladders, playing a role in glomerulation, the team concluded.

• Genetics Researchers Urge Genome-wide Studies for IC and Chronic Prostatitis
  Dimitrakov J, Guthrie D. Genetics and Phenotyping of Urological Chronic Pelvic Pain Syndrome. J Urol. 2009 Feb 19. [Epub ahead of print]
  This review article points out that treatment for IC/painful bladder syndrome and chronic prostatitis/chronic pelvic pain syndrome are still symptom based, and we don’t know the cause or causes.  New ideas are emerging, however, about the role of the sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis and about the genetic basis of these conditions.  Because genome-wide studies have been successful in other diseases where many genes are in play, similar studies in these conditions may also prove successful.  That will depend on carefully defining the patient populations to study, and this article outlines a way to do that.  The authors believe that new methods for studying the whole genome without a bias for any particular set of genes in well-defined patient groups have great potential for making progress in understanding and treating these conditions.

• Sensitive IC Bladder Lining Receptors Point in New Research Direction
  Gupta GN, Lu SG, Gold MS, Chai TC. Bladder urothelial cells from patients with interstitial cystitis have an increased sensitivity to carbachol. Neurourol Urodyn. 2009 Mar 12. [Epub ahead of print]
  Muscarinic receptors are known for the role they play in the bladder muscle because these are the ones that overactive bladder drugs target.  But the receptors exist in bladder lining, too.  And, as these researchers have discovered, the receptors in IC bladders are more sensitive than those in normal bladders.  Adding carbachol, an activator of the receptor, to cultures of bladder lining cells prompted changes in the concentration of calcium ions in the cells. But that change was much greater in IC cells than non-IC cells.  Removing calcium available to the cells or adding an overactive bladder drug erased the difference.  That muscarinic signals may be involved in the IC disease process is a new idea that needs to be investigated further, said the researchers.

• Connection Gets Clearer Between Bladder Inflammation, Pain Transmission
  Hayashi Y, Takimoto K, Chancellor MB, Erickson KA, Erickson VL, Kirimoto T, Nakano K, de Groat WC, Yoshimura N. Bladder hyperactivity and increased excitability of bladder afferent neurons associated with reduced expression of Kv1.4 {alpha}-subunit in rats with cystitis. Am J Physiol Regul Integr Comp Physiol. 2009 Mar 11. [Epub ahead of print]
  What’s the connection between inflammation in IC bladders and pain signaling in nerves?  It’s not well known, so this team took a closer look at the function of nerve cells that transmit signals from inflamed bladders.  Nerve cells sensitive to capsaicin (the hot pepper substance) in normal animals had high thresholds for excitation, but those from animals with irritated bladders had low thresholds and abnormal firing patterns as well.  Nerve cells from irritated bladders had fewer of a particular type of potassium channel related to nerve signaling than normal.  These and their other findings, said the authors, suggest that bladder inflammation increases the excitability of nerve cells carrying signals from the bladder by decreasing the expression of this type of potassium channel.  Similar changes in the pain-signaling nerve fibers that are sensitive to capsaicin may contribute to bladder hyperactivity and increased sensitivity to pain caused by bladder inflammation.

• Stress Factors, Gene Modulators May Bring New Theories, Therapies
  Buffington CA. Developmental Influences on Medically Unexplained Symptoms. Psychother Psychosom. 2009 Mar 9;78(3):139-144. [Epub ahead of print]
  This review suggests that developmental factors may play a role in some cases of medically unexplained symptoms.  An example may be perception of threat by a mother that may be transmitted to a fetus when hormones cross the placenta.  The hormones may “program” the stress response system for enhanced vigilance.  Intense stress in early life may have similar effects that are unmasked by other stressors later in life.  Modulation of gene expression may play a role in this process, and new techniques to identify gene modulators may be a helpful research avenue.

• IC Patients More Easily Startled
  Twiss C, Kilpatrick L, Craske M, Buffington CA, Ornitz E, Rodríguez LV, Mayer EA, Naliboff BD. Increased Startle Responses in Interstitial Cystitis: Evidence for Central Hyperresponsiveness to Visceral Related Threat. J Urol. 2009 Mar 13. [Epub ahead of print]
  These researchers take the startle reflex to be a marker of emotional circuits in the brain that may amplify the response to pain.  Thirteen IC patients showed greater responses to a threat (of the application of muscle-stimulating electrodes over the bladder) than 16 healthy patients.  Higher rates of anxiety and depression in the patients didn’t account for the difference.  This supports the idea that this abnormality may be involved in heightened perception of signals from the bladder in IC.

• Women with IC Had Symptoms, Infections as Kids
  Peters KM, Killinger KA, Ibrahim IA. Childhood Symptoms and Events in Women With Interstitial Cystitis/Painful Bladder Syndrome. Urology. 2008 Nov 24. [Epub ahead of print]
  In childhood and adolescence, IC/PBS patients had more urinary tract infections, frequent use of antibiotics, urgency, trouble starting a stream, urinary retention, constipation, and painful defecation than their bladder-healthy counterparts, according to the results of a survey.  Further statistical analysis showed significant differences between the patients and controls in bladder infections in childhood and urinary urgency in adolescence.  The survey compared the health histories of 215 patients diagnosed with IC, 126 "controls" who had IC/PBS symptoms, and 464 controls with no symptoms.  Children with elimination symptoms need to be followed up over the long term to see whether their symptoms progress to IC/PBS; this kind of research will contribute to our understanding of the natural history of IC/PBS, promote its earlier diagnosis, and potentially prevent progression of the disease, said the authors.
  
  
• IC-like Dysfunction Common in Lupus Patients with UTIs
  Duran-Barragan S, Ruvalcaba-Naranjo H, Rodriguez-Gutierrez L, Solano-Moreno H, Hernandez-Rios G, Sanchez-Ortiz A, Ramos-Remus C. Recurrent urinary tract infections and bladder dysfunction in systemic lupus erythematosus. Lupus. 2008;17(12):1117-21.
  Among women with systemic lupus erythematosus (SLE) who have recurrent urinary tract infections (UTIs), most have urinary symptoms including urgency, frequency, nocturia, and pain.  That was the conclusion of these Mexican researchers who looked at urinary symptoms and did urodynamics studies in 10 SLE patients who had recurrent UTIs.  The patients' scores were high on standard IC questionnaires and on an autonomic symptom scale.  Also, urodynamics showed two had small bladder capacity, four had reduced bladder sensation, one had subnormal urinary flow, and two had a significant amount of urine remaining in the bladder after urination.  The urodynamics results suggest that bladder dysfunction may be the reason for recurrent UTIs in SLE patients, said the authors.
  
  
• Pain Itself May Spread Inflammation, Damage
  Fiorentino PM, Tallents RH, Miller JN, Brouxhon SM, O'Banion MK, Puzas JE, Kyrkanides S. Spinal interleukin-1beta in a mouse model of arthritis and joint pain. Arthritis Rheum. 2008 Oct;58(10):3100-9.
  An intriguing new study on arthritis may have implications for IC because it sheds new light on the nerve "crosstalk" that may occur between different sites in the body in chronic pain conditions.  The discovery is that the nerve processing of pain itself from arthritic joints may actually transfer inflammation to new joints, worsening and expanding arthritis in the body.  That may be another reason not to tough out pain, especially in the early stages of a pain condition, so that it doesn't expand.
  
  University of Rochester (New York) researchers developed genetically engineered mice in which they could induce production of the inflammatory protein interleukin 1-beta (IL-1beta) in the jaw.  When they did, the levels of IL-1beta also went up in the nerve roots at the spinal cord.  In addition, when the researchers induced higher levels of IL-1beta in spinal cord cells, that caused more arthritis symptoms in joints.  Apparently, it is the nervous system that spreads inflammation from one joint to another.
  
  Experimentally interfering with IL-1beta signaling reversed the effects.  Some existing drugs for rheumatoid arthritis act similarly, and the researchers are looking at these drugs as a treatment, not just for rheumatoid arthritis, but also for osteoarthritis.
  
  
• Gender May Influence IC Symptoms
  Yoshiyama M, Kobayashi H, Araki I, Du S, Zakoji H, Takeda M. Sex-related differences in activity of lower urinary tract in response to intravesical acid irritation in decerebrate unanesthetized mice. Am J Physiol Regul Integr Comp Physiol. 2008 Jul 23. [Epub ahead of print]
  In this study of bladder irritation in animals, males and females showed markedly different symptoms in response to the same irritation.  In general, female bladders were more sensitive to acid irritation, whereas the male urethra was more irritable than the female urethra.  In response to the irritation, both sexes had more bladder spasms, but females' bladder contractions were much more frequent.  Irritation reduced the maximum pressure for voiding but had no effect on the threshold of bladder pressure that caused a voiding contraction in females.  In males, however, the maximum voiding pressure didn't change, but the threshold of pressure that prompted a voiding contraction increased.  Male mice also had persistent dribbling of fluid after voiding, whereas females did not.  Finding out why males and females respond differently to bladder irritation might reveal more about the nature of IC.