Social stress-induced bladder dysfunction: potential role of corticotropin-releasing factor

Abstract

Wood SK, Baez MA, Bhatnagar S, Valentino RJ. Social stress-induced bladder dysfunction: potential role of corticotropin-releasing factor. Am J Physiol Regul Integr Comp Physiol 296: R1671-R1678, 2009. First published May 11, 2009 doi:10.1152/ajpregu.91013.2008.-Psychological stress can impact on visceral function with pathological consequences, although the mechanisms underlying this are poorly understood. Here we demonstrate that social stress produces marked changes in bladder structure and function. Male rats were subjected to repeated (7 days) social defeat stress using the resident-intruder model. Measurement of the voiding pattern indicated that social stress produced urinary retention. Consistent with this, bladder size was increased in rats exposed to social stress. Moreover, this was negatively correlated to the latency to assume a subordinate posture, implying an association between passive behavior and bladder dysfunction. In vivo cystometry revealed distinct changes in urodynamic function in rats exposed to social stress, including increased bladder capacity, micturition volume, intermicturition interval, and the presence of non-micturition-related contractions, resembling overactive bladder. In contrast to social stress, repeated restraint (7 days) did not affect voiding, bladder weight, or urodynamics. The stress-related neuropeptide corticotropin-releasing factor (CRF) is present in spinal projections of Barrington's nucleus that regulate the micturition reflex and has an inhibitory influence in this pathway. Social stress, but not restraint, increased the number of CRF-immunoreactive neurons in Barrington's nucleus. Additionally, social stress increased CRF mRNA in Barrington's nucleus. Together, the results imply that social stress-induced CRF upregulation in Barrington's nucleus neurons results in urinary retention and, eventually, bladder dysfunction, perhaps as a visceral component of a behavioral coping response. This mechanism may underlie dysfunctional voiding in children and/or contribute to the development of stress-induced bladder disorders in adulthood.Barrington's nucleus; social defeat; micturition; cystometry; resident intruder CHRONIC OR REPEATED STRESS has numerous adverse psychological and physiological consequences (33). The mechanisms by which stress produces adverse effects have been studied in rodents using a variety of stressors. However, many of these stressors lack ethological validity (i.e., footshock). One stressor that is more ethologically relevant and is currently being used to model stress-related pathology involves social defeat (44). This model, in which a rodent is forced into submission by a larger male conspecific, has been used by several groups to examine behavioral and endocrine consequences of social stress (3,17,24,39,44). A visceral effect of social stress that is often reported, but has not been systematically investigated, is urinary retention that can develop into bladder hypertrophy and even nephropathy due to reflux (10,16,29). The neural processes t...

A corticotropin-releasing factor receptor antagonist improves urodynamic dysfunction produced by social stress or partial bladder outlet obstruction in male rats

“…Thus, discrete chemical activation of Barrington's nucleus neurons elicited bladder contractions that were increased by intrathecal administration of a CRF antagonist, and conversely, decreased by intrathecal CRF. An inhibitory role for CRF in Barrington's nucleus regulation of the bladder is consistent with reports that social stress in rodents leads to urinary retention, abnormal urodynamics, and bladder hypertrophy (4,6,12,13,45), and this is associated with increased expression of CRF in Barrington's nucleus neurons (45). These findings suggest that pharmacological manipulation of CRF may improve bladder dysfunctions associated with stress or other conditions.…”

“…Brain sections collected on slides were postfixed by incubation in 10% formalin and processed to quantify CRF mRNA, as previously described (42). Sections containing Barrington's nucleus were hybridized with an antisense riboprobe to CRF mRNA (Dr. Audrey F. Seasholtz, University of Michigan) and coated with Kodak NTB2 liquid autoradiographic emulsion (7-day exposure at 4°C) identical to that previously published (45). The tissue was lightly stained with cresyl violet, and bright-field images were cap-tured and magnified using Open Lab software to identify cresyl violet-stained cells containing silver grains greater than 2-4 times background.…”

Urothelial Signaling

“…For example, rats exposed to various types of stress (water avoidance, intruder stress) exhibit symptoms of bladder dysfunction including increased micturition frequency as well as anxiety-like behavior (257,299). Furthermore, an exaggerated acoustic startle response has been demonstrated in both cats diagnosed with FIC as well as in BPS/IC patients (279,296).…”

CRH: The link between hormonal-, metabolic- and behavioral responses to stress

“…Studies on molecular mechanisms through which CRH is stimulated in these areas lag behind compared to that of PVH. It has been shown that psychosocial stress increases CRH mRNA levels in the CeA (Hsu et al 1998, Kalin et al 1994 and laterodorsal (oval) subnucleus of BNST (Makino et al 1999) and in the Barrington's nucleus (Wood et al 2009). Although CRH mRNA is elevated in both of…”

“…Expression of CRH mRNA in these neurons is upregulated in response to stress (Wood et al 2009), but not to ADX (Imaki et al 1991). Increase of CRH in Barrington's nucleus by social stress has been linked to stress-induced bladder disfunction (Wood et al 2009, Wood et al 2013.…”