Acute and chronic pains originating from the urinary bladder are common clinical entities affecting more than 50% of females at some time in their lives. In an attempt to understand urinary bladder hypersensitivity in a translational manner, this ongoing research project has used rodents to define basic neurophysiological elements of bladder sensation at spinal and supraspinal levels. Using urinary bladder distension (UBD)-evoked reflexes and spinal/supraspinal neuronal responses as experimental endpoints, clinically-relevant models of bladder hypersensitivity have been developed. Whereas the effect of inflammation as an exacerbator of pain has been investigated, the effects of acute stress have not. The present set of studies seeks to reverse the deficit of knowledge that exists in relation to the mechanisms of acute stress as an exacerbator of urinary bladder pain by performing systematic experimental investigations in our translational model. Further, it seeks to explore novel therapeutics in the form of GABAB-receptor based mechanisms.
Three Specific Aims are proposed:
Specific Aim #1 : To quantitatively characterize effects of serotonergic receptor antagonists on reflex and neuronal responses to UBD in rats which experienced neonatal bladder inflammation (NBI) and subsequently received acute footshock (aFS).
Specific Aim #2 : To quantitatively characterize using immunohistochemical and neurochemical measures, serotonergic agonist and receptor content in the spinal cord of rats which experienced NBI subsequently subjected to aFS.
Specific Aim #3 : To quantitatively characterize central nervous system effects of GABAB receptor agonists and antagonists on reflex and neuronal responses to UBD in rats which experienced NBI in the presence of exacerbating factors (inflammation, aFS). These studies will expand upon preliminary studies and will determine quantitatively the effects of the classic stressor, intermittent nonpainful footshock, on reflex (visceromotor) and spinal dorsal horn neuronal responses to UBD. Effects of pharmacological manipulations related to pain facilitation will be assessed in animals which experienced neonatal bladder inflammation and controls. The proposed studies examining acute stress-related effects in rodent model systems will give insight related to the effect of an acute exacerbating factor related to bladder pain and will explore novel therapeutics. An improved understanding of sensory processing related to IC and of urinary bladder sensory pathways and their modulation by acute stress will result in an increased translation of basic science to therapeutics for bladder pain.
The proposed studies examining acute stress-related effects in rodent model systems will give insight related to the effect of an acute exacerbating factor related to bladder pain. Neural pathways and mechanisms related to an acute stressor - footshock - will be defined. Novel therapeutics related to GABAB-receptor mechanisms will be explored. An improved understanding of sensory processing related to IC and of urinary bladder sensory pathways and their modulation by acute stress and pharmacological manipulations will result in an increased translation of basic science to therapeutics for bladder pain.
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