5HT increases excitability of nociceptor-like rat dorsal root Na+ channels

The physiological effects of 5HT receptor coupling to TTX-resistant Na+ cur rent, and the signaling pathway involved, was studied in a nociceptor-like subpopulation of rat dorsal root ganglion (DRG) cells (type 2), which can b e identified by expression of a low-threshold, slowly inactivating A-curren t. The 5HT-mediated increase in TTX-resistant Na+ current in type 2 DRG cel ls was mimicked and occluded by 10 muM 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, perfusi on 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 inh ibitor 3-isobutyl-L-methylxanthine (200 muM) also mimicked the effect of 5H T on Na+ current, suggesting tonic adenylyl cyclase activity. 5HT reduced t he amount of current required to evoke action potentials in type 2 DRG cell s, 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.