5HT Increases Excitability of Nociceptor-Like Rat Dorsal Root Ganglion Neurons Via cAMP-Coupled TTX-Resistant Na⁺Channels

Abstract

The physiological effects of 5HT receptor coupling to TTX-resistant Na(+) current, and the signaling pathway involved, was studied in a nociceptor-like subpopulation of rat dorsal root ganglion (DRG) cells (type 2), which can be identified by expression of a low-threshold, slowly inactivating A-current. The 5HT-mediated increase in TTX-resistant Na(+) current in type 2 DRG cells was mimicked and occluded by 10 microM forskolin. Superfusion of type 2 DRG cells on the outside with 1 mM 8-bromo-cAMP or chlorophenylthio-cAMP (CPT-cAMP) increased the Na(+) current, but less than 5HT itself. However, perfusion of the cells inside with 2 mM CPT-cAMP strongly increased the amplitude of control Na(+) currents and completely occluded the effect of 5HT. Thus it appears that the signaling pathway includes cAMP. The phosphodiesterase inhibitor 3-isobutyl-L-methylxanthine (200 microM) also mimicked the effect of 5HT on Na(+) current, suggesting tonic adenylyl cyclase activity. 5HT reduced the amount of current required to evoke action potentials in type 2 DRG cells, suggesting that 5HT may lower the threshold for activation of nociceptor peripheral receptors. The above data suggest that serotonergic modulation of TTX-resistant Na(+) channels through a cAMP-dependent signaling pathway in nociceptors may participate in the generation of hyperalgesia.

Acute p38-Mediated Modulation of Tetrodotoxin-Resistant Sodium Channels in Mouse Sensory Neurons by Tumor Necrosis Factor-α

“…There was no significant reduction in current amplitude in the presence of TTX. This is in agreement with previous studies showing that rat DRG neurons that express a prominent I A also express only TTX-resistant Na ϩ currents (Cardenas et al, 1999(Cardenas et al, , 2001). The peak current value at multiple potentials was recorded to generate I-V curves (Fig.…”

Effects of PKC and PKA Inhibitors on the cAMP-Stimulant-Induced Enhancement of Tetrodotoxin-Resistant Na+ (Nav1.8) Currents

“…Similarly, we found that application of 0.5 μM Ro-31-8425 application blocked an increase in Nav1.8 currents induced by either 8-Br-cAMP or the cAMP analogue forskolin [23]. This was supported by the fact that application of a PKC inhibitor (staurosporine or PKC [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] ) caused a marked inhibition of the forskolin-induced increase in the G V1/2 base (i.e. the percentage change in G at baseline V 1/2 ) [24,36,46].…”

“…The application of the PKC inhibitor PKC [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] significantly suppresses the forskolin-induced increase in the Nav1.8 current but the PKA inhibitor WIPTIDE has no significant effect on the PKC activator phorbol12, 13-dibutyrate (PDBu)-induced increase in the current [36]. When considering these results together, it is possible that PKCinduced phosphorylation of the channel protein at serine 1506 is required to enable PKA-induced phosphorylation of other sites on the channel protein suggested by Li et al [40] in a relationship between PKC and PKA on the convergent regulation of Na + channels.…”

“…The VGSC into the skeletal and cardiac muscles is not significantly affected by the activation of PKA [33,34]. However, there are increasing evidences that the enhancement of Nav1.8 currents is seen after the application of hyperalgesic inflammation mediators, such as PGE 2 and serotonin, in sensory neurons [7,[35][36][37]. In fact, PGE 2 application can enhance the responsiveness of primary nociceptive neurons to bradykinin and/or capsaicin [38].…”

TRPV1 Function in Mouse Colon Sensory Neurons Is Enhanced by Metabotropic 5-Hydroxytryptamine Receptor Activation

“…Although sev-eral studies have demonstrated effects of metabotropic 5-HT receptors on voltage-dependent ion channels in neurons (Braha et al, 1993;Torres et al, 1995;Cardenas et al, 2001), the mechanisms by which G-protein-coupled 5-HT receptors trigger action potentials are not known (Christian et al, 1989;Cardenas et al, 1997a,b). An attractive target is the TRPV1 channel, a proton and heat-gated channel that is also activated by endogenous lipid mediators and the pungent vanilloid capsaicin.…”