Inflammation and inflammatory control in interstitial cystitis/bladder pain syndrome: Associations with painful symptoms

Schrepf, Andrew; O’Donnell, Michael A.; Luo, Yi; Bradley, Catherine S.; Kreder, Karl J.; Lutgendorf, Susan K.

doi:10.1016/j.pain.2014.05.029

Cited by 81 publications

(84 citation statements)

References 40 publications

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“…Candidate markers include changes in pain processing networks identified through functional magnetic resonance imaging (fMRI), and hyperalgesia/allodyina identified by quantitative sensory testing (QST), both of which have identified abnormal responses to stimuli in chronic pain patients, including patients with IC/BPS (Kilpatrick et al, 2014; Ness et al, 2014). Another promising biomarker is the inflammatory response to Toll-Like Receptor (TLR) stimulation in peripheral immune cells, as we have recently found these responses to be associated with heightened pelvic pain in IC/BPS (Schrepf et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

“…PBMCs have been hypothesized to mark pain sensitization in humans since it was demonstrated that proliferation of PBMCs incubated with morphine is strongly associated with tolerance for noxious cold stimuli (Hutchinson et al, 2004). Additionally, we found that IC/BPS patients had higher serum levels of Interleukin (IL)-6, a marker of systemic inflammation, and altered diurnal cortisol patterns (Schrepf et al, 2014). These finding echo a recent investigation that found that TLR-2 and TLR-4 inflammatory responses in PBMCs differentiate chronic pain patients from healthy controls (Kwok et al, 2012) and other work identifying altered TLR inflammatory responses as features of other conditions characterized by persistent pain such as Inflammatory Bowel Disease and Rheumatoid arthritis (Kovarik et al, 2011; Kowalski et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Toll-like Receptor 4 and comorbid pain in Interstitial Cystitis/Bladder Pain Syndrome: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain research network study

Schrepf

Bradley

O’Donnell

et al. 2015

Brain, Behavior, and Immunity

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Background Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a condition characterized by pelvic pain and urinary symptoms. Some IC/BPS patients have pain confined to the pelvic region, while others suffer widespread pain. Inflammatory processes have previously been linked to pelvic pain in IC/BPS, but their association with widespread pain in IC/BPS has not been characterized. Methods Sixty-six women meeting criteria for IC/BPS completed self-report measures of pain as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP), collected 3 days of saliva for cortisol assays, and provided blood samples. Peripheral blood mononuclear cells (PBMCs) were stimulated with Toll-Like Receptor (TLR) 2 and 4 agonists and cytokines were measured in supernatant; IL-6 was also measured in plasma. Associations between inflammatory variables and the likelihood of endorsing extra-pelvic pain, or the presence of a comorbid syndrome, were tested by logistic regression and General Linear Models, respectively. A subset of patients (n=32) completed Quantitative Sensory Testing. Results A one standard deviation increase in TLR-4 inflammatory response was associated with a 1.59 greater likelihood of endorsing extra-pelvic pain (p = .019). Participants with comorbid syndromes also had higher inflammatory responses to TLR-4 stimulation in PBMCs (p = .016). Lower pressure pain thresholds were marginally associated with higher TLR-4 inflammatory responses (p = .062), and significantly associated with higher IL-6 in plasma (p = .031). Conclusions TLR-4 inflammatory responses in PBMCs are a marker of widespread pain in IC/BPS, and should be explored in other conditions characterized by medically unexplained pain.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Toll-like Receptor 4 and comorbid pain in Interstitial Cystitis/Bladder Pain Syndrome: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain research network study

Schrepf

Bradley

O’Donnell

et al. 2015

Brain, Behavior, and Immunity

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“…Visceral pain is the most debilitating symptom of painful bladder syndrome (PBS), which affects 7–8 million patients/year in the U.S. alone (Selo-Ojeme and Onwude, 2004; Stanford et al, 2007; van de Merwe et al, 2008; Schrepf et al, 2014). Little is known about pathophysiological mechanisms underlying this disorder, and no treatment or combination of treatments is consistently effective in alleviating symptoms in PBS patients (Selo-Ojeme and Onwude, 2004; Stanford et al, 2007; van de Merwe et al, 2008; Schrepf et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Little is known about pathophysiological mechanisms underlying this disorder, and no treatment or combination of treatments is consistently effective in alleviating symptoms in PBS patients (Selo-Ojeme and Onwude, 2004; Stanford et al, 2007; van de Merwe et al, 2008; Schrepf et al, 2014). Endocannabinoids, such as N -arachidonylethanolamine (AEA, also called anandamide), exert potent analgesic and anti-inflammatory effects (Alvarez-Jaimes and Palmer, 2011; Maione et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Hillard

et al. 2014

J Mol Neurosci

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Endocannabinoids, such as N-arachidonylethanolamine (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 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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“…Studies on cytokines in blood plasma and cerebrospinal fluid of chronic pain patients document low levels of both pro-inflammatory and anti-inflammatory cytokines [5][6][7][8]. Antiinflammatory as well as pro-inflammatory cytokines are produced in all organs in the body in order to achieve a balance between inflammatory and anti-inflammatory mediators in the cells.…”

Section: Difficulties Achieving Relevant Results In Measuring Pro-infmentioning

confidence: 99%

Plasma pro-inflammatory markers in chronic neuropathic pain: Why elevated levels may be relevant for diagnosis and treatment of patients suffering chronic pain

Hanssoń

Breivik

2016

Scandinavian Journal of Pain

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Inflammation and inflammatory control in interstitial cystitis/bladder pain syndrome: Associations with painful symptoms

Cited by 81 publications

References 40 publications

Toll-like Receptor 4 and comorbid pain in Interstitial Cystitis/Bladder Pain Syndrome: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain research network study

Toll-like Receptor 4 and comorbid pain in Interstitial Cystitis/Bladder Pain Syndrome: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain research network study

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

Plasma pro-inflammatory markers in chronic neuropathic pain: Why elevated levels may be relevant for diagnosis and treatment of patients suffering chronic pain

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