The role of the amygdala in anxiety-linked visceral hypersensitivity

Irritable bowel syndrome (IBS) is characterized by symptoms of abdominal pain and abnormal bowel patterns that are often triggered or exacerbated during periods of stress and anxiety. However, the relationship between the neurobiology of anxiety and gastrointestinal physiology is poorly understood and may in part explain the uncharacterized etiology of IBS. The amygdala is an important structure for regulating anxiety and the central nucleus of the amygdala facilitates the activation of both the hypothalamic-pituitary-adrenal axis and autonomic nervous system in response to stress. Therefore, the overarching theme of this dissertation was to determine how hormonal modulation of the amygdala leads to increased indices of anxiety and amplified pain responses with the hypothesis that increasing the gain of the amygdala to induce anxiety-like behavior using corticosterone or chronic stress increases responsiveness to both visceral and somatic stimuli in rodents. This hypothesis was addressed with three specific aims: (1) test the hypothesis that CORT in the amygdala mediates anxiety and altered pain sensitivity, (2) investigate the relative involvement of glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) in CORT-mediated effects and define their specific contributions to anxiety and pain processing, and (3) examine whether there are sex differences in anxiety and pain hypersensitivity by investigating the contribution of ovarian steroids in the amygdala. To pharmacologically isolate the amygdala, micropellets were stereotaxically administered to bathe the dorsal margin of the amygdala while avoiding contact with surrounding structures involved in stress responsiveness. Anxiety-like behavior was quantified by decreased exploration of open areas in the elevated plus maze; additionally, behavioral pain responses to mechanical stimulation of the hind paw and luminal distension of the colon were utilized to assess somatic and visceral pain sensitivity, respectively. These studies yielded novel findings that may help to elucidate the link between anxiety and pain. Specifically, amygdala hyperactivity coupled with elevated levels of corticosteroids acting through glucocorticoid and mineralocorticoid receptors amplify central corticotropin releasing factor signaling and may represent an essential aspect of long-term changes in emotional behavior and nociceptive processing. This new information about the neurobiological basis for the association between stress, anxiety, and the exacerbation of functional visceral and somatic pain represents a significant step forward in identifying new therapeutic targets for chronic pain and affective disorders.