Acute and chronic pains originating from the urinary bladder are common clinincal entities. Some conditions are easy to treat, but others such as interstitial cystitis have proved resistant to diagnosis and treatment. Interstitial cystitis can be described as a visceral neuropathic pain, a hypersensitivity state that is secondary to a site of irritation (a peripheral generator) located in the urinary bladder. It has been estimated to afflict 90,000-450,000 Americans, mainly women. Frustrated and at a loss for effective treatments, some patients have undergone surgical removal of their bladders, only to have continued pain. Attempts to understand and treat this disorder have examined the peripheral generator. This application proposes to extend our field of interest to the spinal sites of sensory processing which may magnify and prolong the effects of peripheral processes. The hypothesis central to the proposed studies is the following: Urinary bladder pain occurs secondary to a N-methyl-D-aspartate glutamate receptor-mediated, spinal, sensitization process produced by repeated or continuous primary afferent activation which leads to a hypersensitivity state in which previously innocuous stimuli produce pain. To test the critical elements of this hypothesis, the elements of spinal visceral nociceptive processing will be defined in halothane- anesthetized, female rats utilizing methodology developed in studies of gut sensation. Studies of primary afferent nerve pathways and physiologic responses in the rat will generate necessary parallel information that will allow for proper interpretation of spinal neuronal data. Neuronal and physiologic responses to urinary bladder distension will also be examined in rats receiving manipulations demonstrated to produce hypersensitivity (inflammation) or prevent hypersensitivity (N- methyl-D-aspartate receptor antagonists) in other model systems. The quantitative studies or urinary bladder sensation proposed in this grant application will test a hypothetical model of visceral nociception and will assess whether a novel group of analgesics, the N-methyl-D-aspartate glutamate receptor antagonists, may have efficacy in the treatment of visceral hypersensitivity states such as interstitial cystitis.
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