Stress is one of the most common experiences, and stress modulates many other experiences including pain. Stress that is perceived as uncontrollable, chronic or unpredictable may, over time, induce long-term pathophysiological changes. Instead of being inhibited, responses to painful stimuli become augmented, a phenomenon known as stress-induced hyperalgesia (SIH). While SIH is associated with multiple painful diseases, including disorders of the urinary bladder, at present it has no mechanistic explanation. The proposed studies will test one potential mechanism related to stress-induced neuropeptide release. Using the urological pain model that is central to the current research in the laboratory, we will test the hypothesis that stress induces release of spinal urocortins which activate spinal corticotropin-releasing factor-2 (CRF-R2) receptors to modulate spinal nociceptive transmission from the urinary bladder. The specific subhypotheses that refine and develop the general hypothesis will be tested in the following specific aims:
Specific Aim 1 will determine the source of urocortins to the spinal dorsal horn.
Specific Aim 2 will determine whether chronic stress alters expression and release of urocortins in the spinal dorsal horn.
Specific Aim 3 will determine whether chronic stress alters expression of CRF-R2 in the spinal dorsal horn.
Specific Aim 4 will determine whether stress, urocortins and CRF-R2 activation alter urinary bladder sensory processing.
The aims of this proposal will utilize molecular biology, immunohistochemistry, electrophysiology and behavioral techniques to gain a better understanding of SIH in a urological system by dissecting out the role of one of the many possible modulators of pain sensation. Results of studies like these will allow future scientists and clinicians to better treat urological pain, as well as the more global phenomenon of chronic pain.
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