PROSTAGLANDINS AND SENSITIZATIONS OF SENSORY NEURONS

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Pro-inflammatory agents such as the prostaglandins (PG) are known to sensitize sensory neurons to noxious stimulation, resulting in a condition of heightened sensitivity known as hyperalgesia. At present, we know very little about the cellular mechanisms whereby PGs modulate the sensitivity and excitability of sensory neurons and the role PGs play in regulating the intensity or duration of the neurogenic inflammatory response. The studies outlined in this proposal are designed to elucidate those physiological mechanisms and PG-induced alterations in sensory transduction cascades that produce sensitization in sensory neurons of the dorsal root ganglion. The proposed studies utilize isolated sensory neurons of the rat dorsal root ganglion grown in cell culture. This model preparation permits investigation of the cellular mechanisms giving rise to PG-induced sensitization in the absence of potential modulating factors released by other cell types. Thus, the direct actions of pro-inflammatory agents to regulate neuronal excitability can be determined. The actions of PGs and excitatory chemical agents, such as bradykinin and capsaicin, are recorded electrophysiologically through utilization of whole-cell and perforated-vesicle patch-clamp recording techniques. Bradykinin and capsaicin are used to probe the levels of neuronal sensitization and thus elucidate whether PC modulation occurs at the level of second messenger mediated cascades or directly at the neuronal membrane. Initial studies will establish a fundamental understanding of the electrophysiological properties of the neuronal responses to bradykinin and capsaicin. This cellular response forms the basic probe to examine the state of neuronal sensitization. Subsequent studies, will further characterize the essential parameters required to produce PG-induced sensitization, such as PG concentration, type of PG, and the time course of PG action. Finally, we will establish the role of PG activation of second messenger- mediated transduction cascades in the physiological mechanisms regulating excitability or sensitivity of the response in sensory neurons. These studies should provide a basic understanding of the cellular mechanisms regulating sensory neuron excitability and the roles these processes play in the initiation and maintenance of neurogenic inflammation. This should also contribute to our understanding of chronic or long-term modifications of neuronal activity such as in long- term potentiation and facilitation. Ultimately, if we can isolate the ionic conductance)s) and establish the regulatory mechanisms producing this enhanced excitability, it will be possible to design drugs that selectively block this conductance or the altered pathway and thus, curb the pain and heightened sensitivity associated with chronic inflammatory conditions, such as rheumatoid arthritis.