The neural aspects of the inflammatory response are mediated by the sensory neurons innervating those affected tissues. Pro-inflammatory agents such as prostaglandins are known to sensitize these neurons to subsequent stimulation, resulting in a condition of heightened sensitivity. Little is known about the cellular mechanisms whereby prostaglandins modulate the sensitivity and excitability of sensory neurons and how this contributes to the intensity or duration of the neurogenic inflammatory response. My research investigates the intracellular transduction cascades that give rise to this sensitization in isolated sensory neurons of the dorsal root ganglion.
We utilize patch-clamp recording techniques to measure the actions of pro-inflammatory agents on membrane currents elicited by excitatory chemical agents, such as capsaicin, or electrical stimulation. Thus, by using the patch-clamp technique, we can investigate the mechanisms whereby second messenger systems and their corresponding pathways regulate membrane excitability at either the level of the whole cell or the single ion channel. We found that this enhanced excitability results from activation of the cyclic AMP pathway through a phosphorylation reaction involving protein kinase A.
Currently we are examining the effects of neurotrophins, like NOF, to modulate the excitability of sensory neurons through the activation of the sphingomyelinase signaling cascade. The goals of our work are to establish how the modulation of various membrane currents alters the excitability of the neuronal membrane. Using molecular approaches, we are also exploring the notion that conditions of long-term inflammation alter gene expression, which can change the complement of ion channels and ultimately lead to a lasting enhancement of neuronal excitability. Mechanisms of Sensitization of ion channel responses in sensory neurons associated with inflammation.
