Tetrodotoxin-resistant Na+ currents and inflammatory hyperalgesia

Several mechanisms have been identified that may underlie inflammation-indu ced sensitization of high-threshold primary afferent neurons, including the modulation of voltage- and Ca2+-dependent ion channels and ion channels re sponsible for the production of generator potentials. One such mechanism th at has recently received a lot of attention is the modulation of a tetrodot oxin (TTX)-resistant voltage-gated Na+ current. Evidence supporting a role for TTX-resistant Na+ currents in the sensitization of primary afferent neu rons and inflammatory hyperalgesia is reviewed. Such evidence is derived fr om studies on the distribution of TTX-resistant Na+ currents among primary afferent neurons and other tissues of the body that suggest that these curr ents are expressed only in a subpopulation of primary afferent neurons that are likely to be involved in nociception. Data from studies on the biophys ical properties of these currents suggest that they are ideally suited to m ediate the repetitive discharge associated with prolonged membrane depolari zations. Data from studies on the effects of inflammatory mediators and ant inociceptive agents on TTX-resistant Na+ currents suggest that modulation o f these currents is an underlying mechanism of primary afferent neuron sens itization, In addition, the second-messenger pathways underlying inflammato ry mediator-induced modulation of these currents appear to underlie inflamm atory mediator induced hyperalgesia. Finally, recent antisense studies have also yielded data supporting a role for TTX-resistant Na+ currents in infl ammatory hyperalgesia. Although data from these studies are compelling, dat a presented at the Neurobiology of Pain colloquium raised a number of inter esting questions regarding the role of TTX-resistant Na+ currents in inflam matory hyperalgesia; implications of three of these questions are discussed .