Functional and inflammatory bowel disorders are characterized by altered perception of visceral sensations. These alterations typically manifest as allodynia. the perception of a normally non-painful stimulus as painful, and hyperalgesia, an enhanced perception of pain. The majority of patients with functional visceral disorders, such as irritable bowel syndrome (IBS), do not have detectable structural or inflammatory changes that might explain the chronic visceral hyperalgesia to mechanical stimuli. In these disorders, nociceptive nerve terminals in the intestine may undergo chronic peripheral sensitization in the absence of tissue injury or inflammation. Several mechanisms underlying peripheral sensitization in the context of tissue injury and inflammation have been identified. What role any of these have in non-inflammatory peripheral sensitization is hampered by an understanding of the basic mechanisms involved in the transduction of noxious mechanical stimuli. Thus the transducer and the mediators involved in nociceptive mechanotransduction are unknown. Based on the preliminary results, NMDA receptors (NMDARs) expressed on peripheral terminals of extrinsic primary afferent nerves (EPANs) are likely to be involved in normal and pathological pain perception. The long-range goal of this application is to determine the role of peripheral NMDARs in visceral pain transmission and in the development of peripheral sensitization. Using a combination of in vivo, in vitro and ex vivo techniques, this proposal addresses the following 4 main hypotheses: 1) EPANs innervating the normal rat colon express functional NMDARs on their peripheral terminals; 2) NMDARs expressed on colonic EPANs differ structurally and functionally from NMDARs expressed in the central nervous system; 3) normal visceral pain responses to transient noxious mechanical stimulation of the colon involve activation of NMDARs on peripheral terminals of colonic EPANs; and 4) activation of NMDARs by sustained noxious stimuli alters the response properties of EPAN terminals, resulting in peripheral sensitization in the absence of inflammation.
Aim 1 will characterize EPANs expressing different subunits of the NMDAR using molecular and immunological approaches.
Aim 2 will characterize the functional properties of NMDAR in DRG neurons in vitro using primary cultures of adult DRG neurons and tissues slices from the colon.
Aim 3 will identify the role of NMDAR in distension mediated EPAN activity in vivo and ex vivo.
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