Christian Twiss, MD,^† Lisa Kilpatrick, PhD,^‡ Veronica Triaca, MD,^† Valerie Arboleda, BA,^† Michelle Craske, PhD,* Hana Ibrahimovic, BA,^‡ Shlomo Raz, MD^†, Emeran A. Mayer, MD,^‡ Edward Ornitz, MD,** Bruce D. Naliboff, PhD,^‡ Larissa V. Rodríguez, MD^†

David Geffen School of Medicine at UCLA and Departments of Urology^†, Psychology*, and Psychiatry and Biobehavioral Sciences**, and The UCLA –VA Center for Neurovisceral Sciences and Women’s Health^‡, Los Angeles, CA

Introduction: The pain of interstitial cystitis (IC) appears to be a visceral pain syndrome with a significant central and neuropathic component. The overlap of IC with other conditions such as irritable bowel syndrome suggests sensitization to visceral stimuli via upregulation of central pathways of pain perception. The startle blink reflex (SBR) is a defensive reflex consisting of an involuntary eye-blink in response to sudden intense stimuli. This reflex is directly modulated by outputs from the amygdala, a component of the limbic system which is involved in the modulation of emotional states (i.e. fear or anxiety) and physical sensations (i.e. pain). Increases in SBR magnitude represent an objective, non-invasive index of affective response to specific stimuli, such as threat of pain. In order to test the hypothesis that IC patients have a possible upregulation of central pain modulation pathways, we compared the SBRs of healthy controls with that of IC patients.

Methods: SBRs were examined for 6 female IC patients and 19 healthy female controls under alternating threat and safe periods. During threat periods, subjects were warned that they may receive aversive electrical stimulation to their bladder region. Each threat period consisted of an early and late phase. If stimulation was to occur, it would occur during the late phase. No electrical stimulation was given during safe periods. To maintain anticipation, stimulation of moderate intensity was given once. SBRs (assessed by electromyographic response of the orbicularis oculi muscle following a 50 ms burst of white noise at 105dB) were measured during all phases. Mixed-effects analysis for repeated measures was applied to determine the influence of diagnosis (IC, Control), threat (Danger, Safe) and phase (Early, Late) on the square-root transformed SBRs.

Results: Significant main effects were observed for diagnosis (p=.008), threat (p<.001), and phase, (p<.001) as well as an interaction between all 3 parameters (p=.045). Patients with IC had significantly greater estimated mean SBRs than controls during early and late safe periods (mean+SE SBR 12.4+1.1 vs. 8.5+0.6, p=0.003, and 12.7+1.1 vs. 9.3+0.6, p=0.01, respectively) and during the early danger period (13.9+1.1 vs. 9.7+0.6, p=0.001, respectively). During the late danger period the SBRs of IC patients and controls were similar (15.1+1.1 vs. 14.1+0.6, p=0.46, respectively).

Conclusions: This initial data indicates that patients with IC have significantly greater SBRs than controls during baseline and during the non-imminent threat periods of the study. This pattern of a heightened startle response in the context of a threat, but not during the imminent threat of pain is indicative of an enhanced context-potentiated startle reflex in IC patients. A similar alteration of the startle reflex has been observed in humans with anxiety disorders and post-traumatic stress disorder. This data provides objective evidence that patients with IC may have upregulation of limbic responses involved in anxiety and stress which can in turn lead to altered pain perception and abnormal modulation of ascending afferent pain signals. Further investigation is needed to determine if this upregulation is a causative agent or a secondary effect of the IC disease process.

Supported by NIH grants P50 DK64539, R24 AT002681 and VA Medical Research, and the Fishbein Family IC Research Foundation.

UroToday.com Coverage of SUFU 2007

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