Ice Water Testing Reveals Hypersensitivity in Adult Rats That Experienced Neonatal Bladder Inflammation: Implications for Painful Bladder Syndrome/Interstitial Cystitis

Randich, Alan; Mebane, Hannah; Ness, Timothy J.

doi:10.1016/j.juro.2009.02.107

Cited by 21 publications

(13 citation statements)

References 10 publications

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“…Initial infection with Δ waaL presumably induces hypersensitivity to a subsequent stimulus, perhaps by known mechanisms that upregulate sensory responses [38], whereas SΦ874 may induce such events in a single infection. This is reminiscent of studies where instillation of yeast zymosan into neonatal rats induces adult hypersensitivity and increased bladder content of pain-related neuropeptides [39], [40]. This is also consistent with recent findings by Farmer and colleagues where serial Candida infection resulted in increased peptidergic nociceptor and sympathetic fiber density in vulvar tissue, demonstrating a mechanism for peripheral hypersensitivity to infection [41].…”

Section: Discussionsupporting

confidence: 90%

O-Antigen Modulates Infection-Induced Pain States

et al. 2012

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The molecular initiators of infection-associated pain are not understood. We recently found that uropathogenic E. coli (UPEC) elicited acute pelvic pain in murine urinary tract infection (UTI). UTI pain was due to E. coli lipopolysaccharide (LPS) and its receptor, TLR4, but pain was not correlated with inflammation. LPS is known to drive inflammation by interactions between the acylated lipid A component and TLR4, but the function of the O-antigen polysaccharide in host responses is unknown. Here, we examined the role of O-antigen in pain using cutaneous hypersensitivity (allodynia) to quantify pelvic pain behavior and using sacral spinal cord excitability to quantify central nervous system manifestations in murine UTI. A UPEC mutant defective for O-antigen biosynthesis induced chronic allodynia that persisted long after clearance of transient infections, but wild type UPEC evoked only acute pain. E. coli strains lacking O-antigen gene clusters had a chronic pain phenotype, and expressing cloned O-antigen gene clusters altered the pain phenotype in a predictable manner. Chronic allodynia was abrogated in TLR4-deficient mice, but inflammatory responses in wild type mice were similar among E. coli strains spanning a wide range of pain phenotypes, suggesting that O-antigen modulates pain independent of inflammation. Spinal cords of mice with chronic allodynia exhibited increased spontaneous firing and compromised short-term depression, consistent with centralized pain. Taken together, these findings suggest that O-antigen functions as a rheostat to modulate LPS-associated pain. These observations have implications for an infectious etiology of chronic pain and evolutionary modification of pathogens to alter host behaviors.

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Section: Discussionsupporting

confidence: 90%

O-Antigen Modulates Infection-Induced Pain States

et al. 2012

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“…As a form of reverse translational research to test the validity of our EIL model, we evaluated whether a similar cold sensitivity was present in our rodent model system. When tested as adults, EIL bladder inflammation resulted in significantly increased VMRs to intravesical cold stimuli even in the absence of re-inflammation as an adult [41]. …”

Section: Discussionmentioning

confidence: 99%

Effects of acute adult and early-in-life bladder inflammation on bladder neuropeptides in adult female rats

et al. 2011

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BackgroundThe purpose of the present study was to determine how acute adult and/or prior early-in life (EIL; P14-P16) exposure to bladder inflammation affects bladder content of calcitonin gene related peptide (CGRP) and substance P (SP). Estrous cycle influences were also studied in the adult-treatment conditions.MethodsIn Experiment 1, intravesical zymosan or isoflurane anesthesia alone was administered to adult female rats. Bladders and serum were collected 24 hours later during each phase of the estrous cycle. In Experiment 2, zymosan or anesthesia alone was administered EIL and as adults, with bladder tissue collection 24 h later.ResultsIn general, Experiment 1 showed that bladder content of both CGRP and SP was increased by inflammation. This effect was significant when data were collapsed across all phases of the estrous cycle, but was only significant during proestrus when individual comparisons were made during each phase of estrous. Also, adult bladder inflammation significantly reduced estradiol levels. In Experiment 2, bladder content of CGRP and SP was significantly increased in rats receiving EIL and/or adult inflammation. Bladder weights were also significantly increased by inflammation.ConclusionsThese data indicate that bladder CGRP and SP are maximally increased during the proestrus phase of the estrous cycle in inflamed adult female rats. EIL exposure to bladder inflammation alone can also produce an increase in CGRP and SP lasting into adulthood. Therefore, EIL experience with bladder inflammation may predispose an organism to experience a painful bladder disorder as an adult by increasing primary afferent content of CGRP and/or SP.

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“…One area of study that has garnered much interest over the last decade is the effect of immune challenges experienced in the neonatal period on later pain processing and the development of chronic pain disorders. These reports provide compelling evidence that permanent changes in nociceptive processing may occur as a result of neonatal insults including bladder inflammation41, intraplantar injection of complete Freund’s adjuvant 21 and systemic LPS injection 3. From these studies it is unknown whether microglial responses to the second stimuli were augmented.…”

Section: Introductionmentioning

confidence: 99%

Pain Intensity and Duration Can Be Enhanced by Prior Challenge: Initial Evidence Suggestive of a Role of Microglial Priming

Hains

Loram

Weiseler

et al. 2010

The Journal of Pain

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Activation of spinal microglia and consequent release of pro-inflammatory mediators facilitate pain. Under certain conditions, responses of activated microglia can become enhanced. Enhanced microglial production of pro-inflammatory products may result from priming (sensitization), similar to macrophage priming. We hypothesized that if spinal microglia were primed by an initial inflammatory challenge, subsequent challenges may create enhanced pain. Here, we used a "twohit" paradigm using two successive challenges, which affect overlapping populations of spinal microglia, presented two weeks apart. Mechanical allodynia and/or activation of spinal glia were assessed. Initially, laparotomy preceded systemic lipopolysaccharide (LPS). Prior laparotomy caused prolonged microglial (not astrocyte) activation plus enhanced LPS-induced allodynia. In this "twohit" paradigm, minocycline, a microglial activation inhibitor, significantly reduced later exaggerated pain induced by prior surgery when minocycline was administered intrathecally for 5 days starting either at the time of surgery or 5 days before LPS administration. To test generality of the priming effect, subcutaneous formalin preceded intrathecal HIV-1 gp120, which activates spinal microglia and causes robust allodynia. Prior formalin enhanced intrathecal gp120-induced allodynia, suggesting that microglial priming is not limited to laparotomy and again supporting a spinal site of action. Therefore, spinal microglial priming may increase vulnerability to pain enhancement.

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Ice Water Testing Reveals Hypersensitivity in Adult Rats That Experienced Neonatal Bladder Inflammation: Implications for Painful Bladder Syndrome/Interstitial Cystitis

Cited by 21 publications

References 10 publications

O-Antigen Modulates Infection-Induced Pain States

O-Antigen Modulates Infection-Induced Pain States

Effects of acute adult and early-in-life bladder inflammation on bladder neuropeptides in adult female rats

Pain Intensity and Duration Can Be Enhanced by Prior Challenge: Initial Evidence Suggestive of a Role of Microglial Priming

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