The use of smokeless tobacco products has been associated with an increased incidence of oral inflammation. However, the mechanisms underlying the pro-inflammatory effects of nicotine are unknown. Our preliminary studies indicate that nicotinic receptors are present on sensory neurons and that nicotine potentiates the evoked release of immunoreactive calcitonin gene related peptide (i-CGRP), a neuropeptide known to possess pro-inflammatory properties. These data provide a molecular basis for the ability of nicotine to influence the development of neurogenic inflammation. The multidisciplinary studies proposed here, therefore, will attempt to elucidate the molecular and pharmacological mechanisms whereby nicotine modulates peripheral neuronal function. The proposed research will: 1. Characterize pharmacologically neuronal nicotinic receptors in the trigeminal ganglion. 2. Identify the subunit composition of nicotinic receptor subtypes that are present in the trigeminal ganglion. 3. Determine the mechanisms by which nicotine alters evoked release of iCGRP from sensory neurons. 4. Determine the effect of chronic nicotine treatment on neuronal nicotinic receptor subtype expression in the trigeminal ganglion. 5. Determine the effect of chronic nicotine treatment on the ability of nicotine to alter evoked release of iCGRP from peripheral sensory neurons. Collectively, these specific aims will test the hypothesis that nicotine, acting at the level of the primary sensory neuron, is capable of modulating the development of neurogenic inflammation. To this end, we have developed a model for studying the ability of nicotine to modulate neurogenic inflammation in oral mucosal tissue. As first point of exposure to nicotine with the use of smokeless tobacco as well as cigarettes, the buccal mucosa offer significant, biomedically relevant advantages as a model system for investigations aimed at elucidating the various effects of nicotine in humans. Additionally, with the use of specific pharmacological, immunological and molecular probes for nicotinic receptors, the results should be able to contribute to a basic understanding on a biochemical level for the effects of nicotine on sensory neurons.
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