Although sympathetic fibers are thought to activate peripheral nociceptors in certain chronic injury syndromes, relatively little is known about sympathetic modulation of capsaicin-sensitive fibers under control conditions. Our preliminary data indicate that alpha adrenergic agonists inhibit the initiation of neurogenic inflammation, as measured by reduction of capsaicin-evoked release of the pro-inflammatory neuropeptide calcitonin gene-related peptide (CGRP) from superfused dental pulp. We propose to evaluate the hypothesis that norepinephrine (NE) and neuropeptide Y (NPY), substances released from terminals of sympathetic fibers, inhibit the initiation of neurogenic inflammation. Such actions would be physiologically and clinically significant, since inhibition of nociceptive primary afferent neurons could alter both peripheral secretion of neuropeptides (reducing neurogenic inflammation), and possibly, membrane depolarization under control conditions. Specifically, we will test the hypothesis that alpha- adrenergic agonists and NPY modulate the development of neurogenic inflammation by inhibiting activation of pulpal terminals of capsaicin- sensitive primary afferent fibers, as measured by peripheral release of iCGRP. Our research strategy takes advantage of a uniquely innervated tissue: dental pulp. Application of any physiologic stimulus to human dental pulp, including thermal, osmotic, chemical or mechanical, produces only a pain sensation. Thus, virtually all sensory neurons which innervate pulp appear to be nociceptors. Accordingly, application of drugs to pulpal sensory neurons targets a population of sensory neurons consisting predominantly of nociceptors.
Our specific aims will: 1. Characterize the pharmacological effects of alpha-adrenergic agonists and NPY to modulate the development of neurogenic inflammation, as measured by inhibition of iCGRP secretion from superfused dental pulp. 2. Evaluate the molecular basis for alpha-adrenergic agonists and NPY to directly modulate iCGRP release via interaction with receptors co-localized with the capsaicin-gated ion channel in trigeminal afferent neurons. 3. Determine whether NE and NPY inhibit iCGRP release by a direct mechanism (i.e., activation of receptors expressed on sensory neurons), by an indirect mechanism (i.e., activation of receptors expressed on non-afferent fibers in pulp), or by a combination of the two. 4. Determine whether activation of sympathetic fibers terminating in dental pulp modulates neurosecretion from capsaicin-sensitive fibers. Since dental pulp is innervated primarily by nociceptors and is frequently involved with inflammation and healing, this tissue is a relevant biomedical model system. Moreover, the use of specific pharmacological, immunological and molecular probes for alpha-adrenergic agonists and NPY should contribute to an understanding on a cellular level for the effects of these substances on capsaicin-sensitive neurons and open new avenues of research on the peripheral actions of these compounds. This knowledge base may provide an insight into sympathetic modulation of neurogenic inflammation under control conditions, and provide a basis for future studies aimed at elucidating mechanisms for sympathetic modulation of these fibers under conditions of tissue injury.
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