PRECLINICAL PHENOTYPIC MODELING OF CHRONIC UROLOGIC PELVIC PAIN
(PI: Dr. Jennifer DeBerry; 1R01DK124792-01A1)

Hypersensitivity of the urogenital organs and pelvic region is associated with urologic chronic pelvic pain syndrome (UCPPS; inclusive of interstitial cystitis/painful bladder syndrome and chronic prostatitis). Evidence from animal models demonstrates that central nervous system processing of urogenital/pelvic sensory information may be modified individually by (i) neonatal events that occur during sensory development and that permanently alter neuroanatomical substrates, or (ii) adverse events, such as stress or trauma, experienced during development or adulthood. Both of these phenomena have a high degree of clinical relevance, and there is good reason to believe that consequential alterations in the phenotype and function of primary afferent neurons innervating the urogenital and pelvic region are critical for the development of hypersensitivity and, thus, would serve as targets for therapeutic intervention. The long-term goal of this project is to systematically study changes in primary afferent-to-spinal cord sensory processing of somatic and visceral urogenital structures in clinically relevant animal models of UCPPS. The objective of the current proposal is to systematically examine the effects of neonatal bladder inflammation (NBI) or maternal separation (NMS), alone and in combination with an adult insult of the same class (bladder re-inflammation, acute or chronic stress), on urogenital hypersensitivity and/or widespread pain. The guiding hypothesis that serves as the basis of this proposal is that experiencing early life inflammation or stress alters distinct subclasses of urogenital primary afferent and spinal dorsal horn neurons that, in turn, inhibit or augment urogenital sensitivity in the context of a secondary adult exposure to inflammation or stress. This hypothesis will be addressed in three specific aims using:

1. in vivo reflex behaviors coupled with optogenetic targeting of stratified neuronal populations to determine how NBI or NMS alter primary afferent- driven reflex behaviors,
2. patch-clamp and extracellular in vivo electrophysiology to characterize functional activity within urogenital afferent and spinal dorsal horn neuronal pathways following NBI or NMS, and
3. neurochemistry and optogenetics to identify neurochemical mediators and receptors/transducers in urogenital tissues, primary afferent neurons, and spinal dorsal horn involved in the development of pelvic hypersensitivity.

Link to abstract in NIH ReporterLearn more about Jennifer DeBerry

Quantitative Studies of Urinary Bladder Sensation
(PI: Timothy Ness; R01DK051413 )

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.

Link to abstract in NIH ReporterLearn more about Timothy Ness

OPTOGENETIC DISSECTION OF THE FUNCTIONAL PROPERTIES OF BLADDER AFFERENT POPULATIONS
(PI: Dr. Jennifer DeBerry; K01DK101681)

This study uses optogenetics to examine the mechanisms underlying differences between interstitial cystitis and overactive bladder. It is hypothesized that subpopulations of bladder afferents contribute uniquely to micturition processes and nociception (pain). This hypothesis is being tested by studying afferent subpopulation contributions:

1. using an ex vivo preparation to functionally evaluate intrinsic and mechanical, chemical, and light-evoked response characteristics,
2. to the expression of in vivo micturition and nociceptive reflexes, and
3. to the activation of neurons receiving bladder afferent input in distinct regions of the spinal cord.

Link to abstract in NIH ReporterLearn more about Jennifer DeBerry