Visceral hyperalgesia is a hallmark of the irritable bowel syndrome (IBS), an extremely common disorder, affecting up to 15 percent of the US population with a major socioeconomic impact. Our understanding of the hyperalgesia in functional pain syndromes such as lBS lags behind our knowledge of the mechanisms of other types of visceral pain that are mechanically-induced or caused by inflammatory reactions mainly because of the lack of a valid animal model. Recently, it was shown that functional abdominal pain can be modeled in animals. Colon irritation (CI) in neonatal but not adult rats, can cause a long lasting visceral hyperalgesia that persists long after the initial injury has resolved. In this study, the central hypothesis is that persistent colonic hyperalgesia, residual to neonatal colon irritation, is associated with central neural sensitization maintained by an interactive exchange of information between the spinal cord and thalamus. HYPOTHESIS 1: There exists a postnatal window of time when minimal colon irritation can induce permanent changes in the nervous system that leads to chronic visceral hyperalgesia.
SPECIFIC AIM ] will define this window of time in postnatal development using noxious mechanical distension or chemical irritation of the colon to cause chronic visceral hyperalgesia. HYPOTHESIS 2: The persistent visceral hyperalgesia residual to neonatal CI is maintained by central plastic changes in neuronal sensitivity.
SPECIFIC AIM 2 will demonstrate with immunocytochemistry and electrophysiology, that the chronic visceral hyperalgesia is associated with neuronal sensitization in the spinal cord and the thalamus. HYPOTHESIS 3: The sensitization is maintained in part by neuronal mechanisms involving glutamatergic and peptidergic processes.
SPECIFIC AIM 3 will determine if blockade of glutamate or neurokinin receptors by specific antagonists will reduce the central sensitization. HYPOTHESIS 4: The central sensitization is maintained by an intact dorsal column (DC) participating in a feed-forward dynamic exchange of information between the dorsal horn of the spinal cord and the thalamus.
SPECIFIC AIM 4 will demonstrate, using electrophysiology and behavior studies, that the sensitization is mediated by an intact DC-thalamus communication that maintains thalamic sensitization and amplifies spinal neuronal sensitivity via descending pathways. The long-term objective of the proposed study is to define the neurophysiological correlates of chronic visceral hyperalgesia and hence to identify novel therapeutic targets for the relief of pain in patients with functional bowel disorders.
