Excitability of small-diameter trigeminal ganglion neurons by 5-HT is mediated by enhancement of the tetrodotoxin-resistant sodium current due to the activation of 5-HT4 receptors and/or by the inhibition of the transient potassium current

The aims of the present study were to investigate whether the activation of the 5-HT receptor subtypes (5-HT4 and 5-HT3) acted significantly on the modification of the tetrodotoxin-resistant sodium current (INaR) in small-sized rat trigeminal ganglion (TG) neurons and whether the inhibition of the transient K+ current (IA) contributed to the excitability in those neurons. 5-HT applications in at concentrations ranging from 0.01-10 μM significantly increased the peak INaR. One micromolar 5-HT application caused the greatest increase in the peak INaR amplitude accompanied by a hyperpolarizing shift in the activation curve. A similar modification of INaR properties was also obtained via the application of the 5-HT4 receptor agonist, RS 67333, in concentrations ranging from 0.001-1 μM. The largest effects of 5-HT (1 μM) and RS 67333 (0.1 μM) on the modification of INaR were abolished by pretreatment with ICS 205-930 (a 5-HT3/4 receptor antagonist, 10 μM), which showed no significant effect on the baseline INaR. However, ICS 205-930 application at 30 μM caused a significant decrease in the baseline INaR. Phenylbiguanide (a 5-HT3 receptor agonist) did not significantly alter INaR properties when applied in concentrations ranging from 1 to 100 μM. The application of 0.1 μM RS 67333 decreased the transient K+ current (IA) by approximately 31%. The threshold for action potential generation was significantly lower after the application of 0.1 μM RS 67333. Furthermore, 0.1 μM RS 67333 application increased the number of action potentials and the resting membrane potential got more positive, but it decreased the duration of depolarization phase of action potential. In addition, neither the additional application of 1 μM 5-HT in the presence of 10 μM forskolin, a stimulator of adenylyl cyclase, nor the opposite applications of 5-HT and forskolin caused the enhancement of increased INaR, which indicates the presence of an 'occluding effect.' These results suggest that the 5-HT-induced modification of INaR is mediated by the activation of 5-HT4 receptors, involving a cAMP-dependent signaling pathway, and that the inhibition of IA following the application of a 5-HT4 receptor agonist also contributes to the increased number of action potentials.