This application by a new investigator addresses the molecular consequences of chronic pain and how pain-induced neuronal plasticity alters sensory processing. Neurokinin-1 receptors (NK-1 receptor) and substance P (SP) are as mediators of nociceptive (pain- related) information. Nociception increase NK-1 receptor gene expression in sensory systems. We hypothesize that continued transmission of nociceptive information by substance-P containing neurons produces molecular events that increase gene expression of the NK-1 receptor, increase the sensitivity of NK-1 receptor-expressing neurons in sensory systems, and ultimately enhance the sensitivity of the intact animal to subsequent stimuli.
Specific aims are to: 1) Determine where and when NK-1 receptor gene expression is altered by painful stimuli. NK-1 receptor mRNA levels will be measured in the rat using solution hybridization-nuclease protection assays and in situ hybridization following chemogenic inflammation. Formalin and Freund's complete adjuvant will be used as inflammatory nociceptive stimuli and compared to non-noxious thermal and mechanical stimuli. The sensitivity of evoked NK-1 receptor gene expression to graded doses of NK-1 receptor antagonist drugs will also be assessed. 2) Determine whether painful stimuli increase the functional sensitivity of NK-1 receptor expressing cells. NK- 1 receptor agonist-stimulated [35S]GTPgammaS binding will be used to assess the functional coupling of NK-1 receptor as the initial step in signal transduction following G-protein activation assessed in rats undergoing the inflammatory treatments described above. 3) determine the mechanistic contribution of altered NK-1 receptor gene expression to the behavioral sensitization that develops following persistent pain. The production of a sensitized (hyperalgesic or allodynic) state will be assessed by measuring withdrawal thresholds to mechanical or thermal stimulation of the hindpaws. The sensitivity of inflammation-evoked hyperalgesia or allodynia to graded doses of selective non-peptide NK-1 receptor antagonist drugs will be assessed. Detailed correlative analyses of the effects of NK-1 receptor antagonist drugs on the molecular, cellular and behavioral end points measured will characterize the relationship between molecular and behavioral events regulating NK-1 receptor function. By testing the hypothesis at the level of the gene, the cell, and the intact behaving animal, these experiments will have important consequences on our understanding of the involvement of NK-1 receptor function in the sensitization of the central nervous system by long-term pain, and may identify novel targets or therapies for the control of the pain-enhancing effects of nociception resulting from increased NK-1 receptor gene expression in the spinal cord.
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