The identification of endogenous substances that mediate sensory and synaptic signaling nociceptive pathways has resulted from pharmacological and physiological studies. For a number of these ligand-receptor systems, selective and potent pharmacological probes have not been developed that can discriminate among closely related receptor subtypes. This lack of pharmacological reagents has hampered progress in understanding signaling mechanisms in nociceptive pathways and in the development of novel drug- based therapies for the treatment of acute and chronic pain. The application of molecular biological methods to neuropharmacology has greatly facilitated the identification and functional characterization of distinct receptor subtypes for most neurotransmitters. Gene cloning has also provided molecular probes for determining the location of specific receptor subtypes within functional neural pathways, and their regulation under physiological and pathological conditions. This proposal is focused on the molecular biology of two receptors that are important in sensory transduction and neural transmission in nociceptive pathways. One class of receptors is activated by extracellular adenosine triphosphate (ATP), and the other by vanilloid compounds (e.g., capsaicin and resiniferatoxin). We have recently isolated genes encoding ATP-gated ion channels (termed P/2X receptors) from the mammalian nervous system. We propose to use these molecular probes to determine where these receptors are expressed in the nociceptive pathway. In addition, we plan to elucidate physiological roles for these receptors in sensory transduction and synaptic transmission by generating mutant mice through gene targeting that lack specific ATP receptor subtypes. We are also initiating efforts to isolate a functional cDNA clone encoding the capsaicin receptor, which serves as an important marker for sensory afferents in the pain pathway and which represents a potential target for novel therapeutic agents in the treatment of pain.
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