Peripheral sensitization (i.e. increased sensitivity of sensory neurons) is initiated by the acute inflammatory response, and under pathological conditions this sensitization is maintained producing chronic inflammatory pain. Of major importance in this phenomenon is the production and release of proinflammatory prostaglandins which occurs at the onset of injury and is maintained throughout the course of inflammatory diseases. Although much work has focused on cellular mechanisms mediating the acute sensitizing actions of prostaglandins, there is little understanding of the mechanisms by which these eicosanoids can maintain peripheral sensitization. Recent studies performed in our laboratory suggest a novel mechanism to maintain sensitization, whereby a cooperative interaction occurs between the inflammatory mediator nerve growth factor (NGF) and prostaglandins. Through this mechanism, NGF switches the intracellular signaling cascade that mediates prostaglandin-induced sensitization from the canonical cAMP-dependent protein kinase (PKA) pathway to exchange factors directly activated by cAMP (Epacs). In this way, inflammation (by increasing NGF production and release) enables sensory neurons to continue to respond to prostaglandins over time. Thus, we hypothesize that inflammation or long-term exposure to inflammatory mediators switches the signaling pathways that mediate the sensitizing actions of prostaglandins. To test this hypothesis, we propose three specific aims.
In aim 1, we will determine the mechanism(s) by which NGF switches the intracellular signaling pathways mediating the PGE2-induced peripheral sensitization from activation of PKA to activation of Epacs.
In aim 2, we will determine whether inflammation also switches the intracellular signaling pathways mediating the PGE2-induced peripheral sensitization from cAMP-induced activation of PKA to cAMP-induced activation of Epacs.
In aim 3, we will determine the downstream signaling pathway(s) mediating Epac-induced sensitization of sensory neurons. Overall, the knowledge gained from these studies is critical to understanding the process of sustained pain and hypersensitivity in chronic arthritic diseases. In addition, if we demonstrate that Epac2 activation only occurs during inflammation, our findings have important implications for elucidating a novel therapeutic target for treating chronic pain during inflammation.
Our understanding of the mechanism by which chronic inflammatory pain persists throughout the course of arthritic diseases is limited, as is effective and safe therapy for chronic pain. The studies outlined in this proposal will examine a novel way that the neurons that conduct pain signals adapt during inflammation to become more active (hypersensitive). If we show that a unique pathway exists in pain conducting neurons that make them hypersensitive during inflammation, new and targeted drug therapy can be developed to shut off the pathway and treat chronic inflammatory pain.
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