Cellular mechanisms of neurogenic inflammation.

Since the initial observations that stimulation of sensory neurons produces vasodilation, plasma extravasation, and hypersensitivity, much progress has been made in understanding the etiology of neurogenic inflammation. Studies have focused largely on the role of the neuropeptides, substance P and calcitonin gene-related peptide, which are released in the periphery by activation of small diameter sensory neurons. Recent work, however, has begun to emphasize the cellular mechanisms involved in regulating the release of proinflammatory substances from sensory neurons. In this perspective, discussion centers on a number of inflammatory mediators that activate various signal transduction pathways to augment excitability of and transmitter release from sensory neurons. Emphasis is placed on those pathways where multiple lines of evidence support their importance in initiating neurogenic inflammation. Recent studies, however, support the notion that there are novel compounds released during injury that can stimulate or sensitize sensory neurons. Furthermore, only now are intracellular signaling pathways that have been identified in other cell systems being studied in sensory neurons to establish their role in neurogenic inflammation. The challenge remains to ascertain the critical transduction pathways that regulate transmitter release from sensory neurons since this phenomenon triggers neurogenic inflammation. In addition, the cellular mechanisms involved in alterations in neuronal excitability during injury and the cellular pathways that maintain the inflammatory response over time need to be determined. With these advances, we will be able to develop therapeutic interventions to minimize deleterious consequences of neurogenic inflammation.