Abstract
Mechanisms were studied by which prostaglandin E(2) (PGE(2)) up-regulates Na(+) currents (INa) in medium diameter dorsal root ganglion (DRG) cells that express large T-type Ca(2+) currents (type-4 DRG cells). PGE(2) or the adenylyl cyclase (AC) activator forskolin (10 μM) up-regulated peak INa evoked by test potentials (TP) to -10 mV by an average of 13.5% and 21.8%, respectively. The PGE(2) and forskolin induced up-regulation of INa, evoked with TPs to -10 mV, began approximately 15-20 s after initiation of drug exposure and continued gradually over the course of 2-3 min. Both PGE(2) and forskolin significantly increased peak conductance without significantly shifting the voltage at which INa was ½ activated (V(a)) or ½ steady state inactivated. However, although V(a) was not significantly shifted, both PGE(2) and forskolin induced a proportionally greater percent increase in conductance at weak TPs to around -30 mV compared to stronger TPs to around 10 mV. The PGE(2)-induced up-regulation of INa was occluded by prior up-regulation with forskolin, and the up-regulation of INa by both PGE(2) and forskolin was blocked by Rp-cAMPs and 50 nM tetrodotoxin (TTX). In the presence of Rp-cAMPs, both PGE(2) and forskolin induced decreases in INa that peaked around 25 s following initiation of PGE(2)/forskolin application. The decrease induced by PGE(2) averaged 8.5%, which was significantly greater than the average 3.5% decrease induced by forskolin. Estimation of kinetic rate constants by fitting INa with a Markov channel state model, suggested that both PGE(2) and forskolin up-regulated INa by changing channel gating rather than by increasing channel number or unitary conductance. The data suggest that application of PGE(2) may initially induce a relatively rapid down-regulation of TTX-sensitive INa (signaling pathway uncharacterized), followed by a gradual up-regulation of INa via activation of an AC/PKA-dependent signaling pathway. The up-regulation of INa in sensory neurons with type-4 cell bodies may increase excitability and strengthen signaling, and may play some role in the allodynia and hyperalgesia associated with injury to nerves and peripheral tissues.