Prostaglandin E2 modulates TTX-R INa in rat colonic sensory neurons

This study was performed to determine the impact of the inflammatory mediator prostaglandin E-2 (PGE(2)) on the biophysical properties of tetrodotoxin resistant voltage-gated Na+ currents (TTX-R I-Na)in colonic dorsal root ganglion (DRG) neurons. TTX-R I-Na was studied in DRG neurons from thoracolumbar (TL: T-13-L-2) and lumbosacral (LS: L-6-S-2) DRG retrogradely labeled following the injection of DiIC(18) (DiI) into the wall of the descending colon of adult male rats. TTX-R I-Na in colonic DRG neurons had a high threshold for activation [V-0.5 of conductance-voltage (G-V) curve = -3.1 +/- 1.0 (SE) mV] and steady-state availability (V-0.5 for H-infinity curve = -18.4 +/- 1.4 mV), was slowly inactivating (10.6 +/- 1.4 ms at 0 mV), and recovered rapidly from inactivation (83.5 +/- 5.0% of the current recovered with a time constant of 1.3 +/- 0.1 ms at -80 mV). TTX-R I-Na was present in every colonic DRG neuron studied (n = 62). PGE(2) induced a rapid (<15 s) increase in TTX-R I-Na that was associated with a hyperpolarizing shift in the G-V curve (3.4 +/- 0.7 mV), an increase in the rate of inactivation (4.21 +/- 0.7 ms at 0 mV), and no change in steady-state availability. There was no statistically significant difference (P > 0.05) between TL and LS colonic DRG neurons with respect to the biophysical properties of TTX-R I-Na, the current density or the magnitude of PGE(2)-induced changes in the current. However, both the proportion of TL and LS neurons in which TTX-R I-Na was modulated by PGE(2) (16 of 16 TL neurons and 12 of 14 LS neurons) as well as the magnitude of PGE(2)-induced changes in the current were significantly larger in colonic DRG neurons than in the total population of DRG neurons. These results suggest that changes in nociceptive processing associated with inflammation of the colon does not reflect differences between TL and LS neurons with respect to the properties of TTX-R I-Na, distribution of current, or magnitude of inflammatory mediator-induced changes in the current. However, these results do suggest modulation of TTX-R I-Na in colonic afferents is an underlying mechanism of hyperalgesia and pain associated with inflammation of the colon and that this current constitutes a novel target for therapeutic relief of visceral inflammatory pain.