Tetrodotoxin-resistant Na⁺currents and inflammatory hyperalgesia

Abstract

Several mechanisms have been identified that may underlie inf lammation-induced sensitization of high-threshold primary afferent neurons, including the modulation of voltage-and Ca 2؉ -dependent ion channels and ion channels responsible for the production of generator potentials. One such mechanism that has recently received a lot of attention is the modulation of a tetrodotoxin (TTX)-resistant voltage-gated Na ؉ current. Evidence supporting a role for TTX-resistant Na ؉ currents in the sensitization of primary afferent neurons and inf lammatory hyperalgesia is reviewed. Such evidence is derived from studies on the distribution of TTX-resistant Na ؉ currents among primary afferent neurons and other tissues of the body that suggest that these currents are expressed only in a subpopulation of primary afferent neurons that are likely to be involved in nociception. Data from studies on the biophysical properties of these currents suggest that they are ideally suited to mediate the repetitive discharge associated with prolonged membrane depolarizations. Data from studies on the effects of inf lammatory mediators and antinociceptive agents on TTX-resistant Na ؉ currents suggest that modulation of these currents is an underlying mechanism of primary afferent neuron sensitization. In addition, the second-messenger pathways underlying inf lammatory mediator-induced modulation of these currents appear to underlie inf lammatory mediator-induced hyperalgesia. Finally, recent antisense studies have also yielded data supporting a role for TTX-resistant Na ؉ currents in inf lammatory hyperalgesia. Although data from these studies are compelling, data presented at the Neurobiology of Pain colloquium raised a number of interesting questions regarding the role of TTX-resistant Na ؉ currents in inf lammatory hyperalgesia; implications of three of these questions are discussed.

Neonatal maternal deprivation sensitizes voltage-gated sodium channel currents in colon-specific dorsal root ganglion neurons in rats

“…5C) sodium currents density was greatly enhanced in NMD rats compared with controls. This is in agreement with previous reports that TTX-R sodium current is involved in somatic pain (21) and visceral pain (2,22). Possible mechanisms for the potentiation of TTX-R sodium currents include an increase in single-channel conductance, channel opening probability, and/or upregulation of Na V 1.8 or/and Na V 1.9 expression.…”

Prostaglandin E2 Has No Effect on Two Components of Tetrodotoxin-Resistant Na+ Current in Mouse Dorsal Root Ganglion

“…In conclusion, although it is highly likely that the TTX-R Na V 1.8 subunit plays an important role in PGE 2 -induced sensitization of primary afferent neurons that causes inflammatory hyperalgesia (3,21), a serious question was raised as to the above compelling hypothesis on the role of TTX-R Na + current. Although we do not exclude the possibility that TTX-R Na + channels play an important role in the PGE 2 -induced sensitization, our data suggest that an augmentation of TTX-R Na + current immediately after the PGE 2 treatment may not be a principal event.…”

COX2 in CNS neural cells mediates mechanical inflammatory pain hypersensitivity in mice

“…Release of PGE 2 at the site of peripheral inflammation contributes to pain hypersensitivity by reducing the threshold and increasing the excitability of peripheral terminals of nociceptor sensory fibers. This results from an E prostanoid (EP) receptor-mediated activation of intracellular kinases in the nociceptor terminal that phosphorylate the noxious heat transducer TRPV1 (13,14) and the Na V 1.8 voltage-gated sodium channel (15)(16)(17) to produce peripheral sensitization, a change in thermal sensitivity confined to the area of inflammation. Increases in PGE 2 in the CNS after peripheral inflammation mediate a widespread increase in mechanical pain sensitivity due to synaptic facilitation within the spinal cord (18,19), resulting from increased transmitter release, activation of cation channels, and blockade of glycine receptors (20).…”