The impact of amygdala CGRP receptors on the development of persistent bladder pain.

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PROJECT SUMMARY Urologic chronic pelvic pain syndrome (UCPPS) affects millions of individuals worldwide, and current treatments are limited due to their lack of efficacy. Although the underlying mechanisms of the development and maintenance of visceral pain are poorly understood, visceral pain is thought to engage brain circuits that may contribute to chronicity. The central nucleus of the amygdala (CeA) has received increasing attention as a significant region in the pathology of chronic pain. Findings from both human and rodent studies have revealed hemispheric lateralization of the CeA in pain modulation. While the right CeA has been shown to drive pain in models of somatic and visceral pain, the left CeA has been shown to attenuate visceral bladder pain. Recent evidence has implicated that CeA neuronal activity is not only asymmetric, but also changes with time once neuropathic pain is induced. However, it is unknown whether time-dependent activation of the CeA is prevalent in persistent bladder pain. I aim to further explore the hemispheric and temporal changes of the CeA in the context of bladder sensitization and injury, as well as identify cell-types that might be responsible for driving these changes. Calcitonin gene-related peptide (CGRP) is a neuropeptide that has been shown to produce divergent asymmetric functions within the CeA. In somatic pain, CGRP has been shown to have an antinociceptive function in the left CeA and a pronociceptive function in the right. However, little is understood about the role of CGRP and CGRP receptors in the brain in models of bladder pain. The overall objective of this proposal is to determine the influence of CGRP receptors on bladder pain-related lateralization over time. I will approach this goal by: 1) determining how CGRP receptor positive neurons (located in the right or left CeA) may influence pain-like behavior in two persistent bladder pain models, and 2) studying CeA activity of CGRP projection cells from the left or right parabrachial nucleus (PBn) in awake-behaving mice. Focusing on the contributions of CGRP receptors in visceral pain modulation could provide insight into the underlying mechanisms contributing to pain-related lateralization within the CeA. This, in turn, will lead to the development and advancement of effective CNS targeted therapies for bladder pain.