In contrast to pain of somatic origin, visceral pain has been less well studied and is poorly understood. Separate afferents encode noxious and nonnoxious somatic stimuli. However, most mechanosensitive colonic afferents respond to both noxious and innocuous mechanical stimuli and virtually all mechanosensitive colonic afferents response with thresholds below those considered painful. This application proposes to study the physiology, pharmacology and anatomy of spinal cord neurons that respond to nonnoxious and/or noxious colonic stimuli in order to examine potential strategies the nervous system uses to differentiate painful from nonpainful stimulation of the lower bowl. The long-term goal of this application is to yield a better understanding of the spinal mechanisms that produce visceral sensation in the hope of developing better therapeutic regimens for visceral pain management and ultimately the alleviation of visceral pain syndromes. A well characterized model of visceral stimulation, colorectal distention (CRD), will be used to deliver noxious or nonnoxious intensities of visceral stimulation. Behavioral, anatomical and electrophysiological techniques will be used to test several alternative, though mot mutually exclusive hypotheses in the following specific aims: 1) Test the hypothesis that behavioral and reflex responses to noxious and nonnoxious CRD in awake rats are differentiated, in part, by differences in the relative amount of activity at NMDA, AMPA and NK-1 receptors and that inflammation shifts the contribution of the receptors from the nonnoxious state to the noxious state. 2) Test the hypothesis that the population of neurons that responds to noxious CRD can be differentiated from the population of neurons that responds to nonnoxious CRD on the basis of receptor content. 3) Test the hypothesis that the differentiation of noxious from nonnoxious CRD depends on the number and target of supraspinal projection neurons. 4) Test the hypothesis that the temporal response of dorsal horn neurons contributes to the differentiation of noxious and nonnoxious CRD. Demonstrate that neurons with different temporal response profiles project to different supraspinal targets and the pharmacology of these responses differs to noxious and nonnoxious stimuli.
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