The Role of Amygdala Calcitonin Gene-related Peptide (CGRP) Receptors in the Development of Persistent Bladder Pain

Abstract

The underlying mechanisms of visceral pain (e.g. bladder pain) are poorly understood, making it difficult to treat. The central amygdala (CeA) is known as a significant contributor to the pathology of chronic pain. While the CeA in the right hemisphere has been shown to increase bladder pain, the left CeA has been shown to reduce bladder pain. Recent evidence has shown that CeA activity is not only asymmetric, but also changes with time once somatic pain is induced. However, it is unknown whether time-dependent activation of the CeA contributes to the development of chronic bladder pain. We seek to study the hemispherical and temporal changes of the CeA in the context of bladder pain and identify cell-types that might be responsible for contributing to these changes. One interesting target that has been shown to produce asymmetric functions within the brain is calcitonin gene-related peptide (CGRP). In this study, we used a CGRP antagonist – CGRP8-37, to study the role of CeA CGRP receptors (CGRP-Rs) on bladder pain-related changes over time. The effects of CGRP8-37 were examined using a mouse model of bladder pain (100 mg/kg cyclophosphamide, 3 days). Two pain assays, abdominal von Frey and the voiding spot assay were conducted (2-14 days post-injury) in mice that received direct CeA injections (right CeA) of CGRP8-37 (1 uL of 100uM) or saline. Preliminary data indicate that animals that received saline displayed a decrease in 50% withdrawal threshold (bladder nociception) in the abdominal von Frey assay once treated with cyclophosphamide. Animals that received a direct injection of CGRP8-37 displayed an increase in 50% withdrawal threshold (less nociception) compared to saline treated animals. In the voiding assay, CGRP8-37 led to changes in voiding frequency. Collectively, these data support the study of cell-specific manipulation of the right CeA to produce pain relief. Grant support from 7R01DK115478-04 and 1F32DK128969.