Signalling cascades that modulate the activity of sodium channels in sensory neurons

Abstract

It is well established that inflammatory mediators can heighten the sensitivity to a variety of different modalities of sensory stimulation. Early work demonstrated that inflammatory mediators, such as prostaglandin E2, serotonin, or nerve growth factor, lower the threshold to nociceptive stimuli in animal models of pain. Later work has shown that a large part of this enhanced sensitivity results directly from the altered sensitivity or excitability of the sensory neurons themselves. All of these inflammatory mediators are known to act via membrane receptors, and it comes as no surprise that nociceptive sensory neurons express many of these receptors. Ligand binding to these receptors results in the activation of downstream signalling cascades which can ultimately regulate or modulate the activity of ion channels that are critical in setting the state of excitability in sensory neurons. This review will focus on the signalling cascades that modulate the activity of voltage-dependent sodium channels that give rise to the augmented sensitivity to various kinds of stimuli. This alteration in the sensitivity or threshold will be referred to as sensitization. In addition to modulation of channel activity, another important mechanism that can modify the state of excitability is the transcriptional change that leads to alterations in the levels of expression for different ion channels. Several recent reviews have discussed the changes in sodium channel expression after different types of nerve injury, such as that arising after neuropathic or inflammatory pain states ([1–9] and Chapter by J.J. Clare, this volume), therefore such observations regarding sodium channels will not be discussed.