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

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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 μM 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 μM) 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.