Inflammation-Induced Plasticity in Sensory Neurons

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DESCRIPTION (provided by applicant): Pain resulting from inflammation of is one of the most common reasons people seek medical attention. Inflammatory pain is associated with the sensitization of primary afferent neurons innervating injured tissue; i.e., those arising from trigeminal ganglia (TG) or dorsal root ganglia (DRG). Pain arising from specific structures such as the colon or TMJ is often the most difficult pain to treat possibly reflecting the unique properties of these afferents and/or the unique structures these afferents innervate. Nevertheless, our present understanding of the neurobiology of sensory neurons and their response to injury is derived largely from studies on somatic afferents. In normal tissue, voltage- and Ca2+-activatedchannels present in the plasma membrane of the afferent terminal control afferent excitability. Primary afferent neurons are hyper-excitable in the presence of persistent inflammation. However little is known about the mechanisms underlying this increase in excitability? This is particularly true for visceral and joint afferents given the dearth of data on the basic membrane properties of these afferents innervating normal tissue. One class of ion channels that may be particularly important for the expression of inflammation-induced hyperexcitability is Ca2+activated K+(CaK) channels. Inhibition of CaK channels appears to underlie sensitization of vagal afferents following airway inflammation and our preliminary data suggest that these channels are likely to contribute to inflammation-induced changes in the excitability DRG and TG neurons innervating several structures. Importantly, there have been only two studies on the function of CaK channels in sensory neurons from naive animals and none on the function of CaK channels in sensory neurons from inflamed animals. Therefore, we propose to test the following hypotheses: 1) that the distribution and functional role of CaK channels varies with respect to target of innervation (i.e., colon, TMJ, muscle and skin); and 2) that inflammation results in changes in the pattern of expression of CaK channels, which underlies changes in excitability that are unique to specific targets of innervation. We will test these hypotheses in experiments described under 2 Specific Aims employing a combination of retrograde tracing, in vitro patch-clamp electrophysiology, Ca2+imaging and RT-PCR analysis on adult rats either in the presence of absence of inflammation.