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

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, inter-micturition 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.