Heme oxygenase (HO) catalyzes the conversion of heme to carbon monoxide (CO), biliverdin and iron. While it has long been recognized that HO activity is important for the clearance of excess heme, only recently has it been recognized that the products of heme metabolism may themselves have important and unexpected biological properties. In particular, CO has well-established roles as a second messenger molecule somewhat analogous to those of the gaseous second messenger molecule NO. Based on a review of the available HO literature, a recognition of the functional similarities between HO and nitric oxide synthase (NOS) and data from our own preliminary and published experiments we hypothesize that HO plays important roles in nociceptive signaling. The first experiments proposed will in a systematic and rigorous way document or refute the hypothesis that HO activity is involved in nociceptive signaling in inflammatory, incisional and neuropathic rodent pain models. Tools used in these first experiments include two separate classes of HO inhibitors, and both 110-1 and HO-2 null mutant or """"""""knockout"""""""" strains of mice. From that point we will go on to determine if the expression or enzymatic activity of various HO isotypes is altered by noxious stimuli in dorsal root ganglia (DRG) or spinal cord tissue. These tissues are of paramount importance in nociceptive signal processing. Immunohistochemical and in situ techniques will help us to localize putative changes in HO expression to particular regions or cell types of the spinal cord and DRG's. Finally, we will explore the neurochemical mechanism responsible for the increase in spinal cord HO enzymatic activity after noxious stimulation using a series of selective receptor antagonists directed against major types of spinal cord receptors involved in nociceptive signal transmission, namely the NMDA, AMPA and NK- 1 receptors. The information collected during the course of these studies will greatly contribute to our scientific understanding of HO's roles in nociceptive signaling, and will help us to determine if drugs which alter HO activity might be useful as analgesic compounds in a number of different clinical situations.
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