5HT(4) RECEPTORS COUPLE POSITIVELY TO TETRODOTOXIN-INSENSITIVE SODIUM-CHANNELS IN A SUBPOPULATION OF CAPSAICIN-SENSITIVE RAT SENSORY NEURONS

The distribution of tetrodotoxin (TTX)-sensitive and -insensitive Nacurrents and their modulation by serotonin (5HT) and prostaglandin E-2 (PGE(2)) was studied in four different types of dorsal root ganglion (DRG) cell bodies (types 1, 2, 3, and 4), which were previously identi fied on the basis of differences in membrane properties (Cardenas et a l., 1995). Types 1 and 2 DRG cells expressed TTX-insensitive Na+ curre nts, whereas types 3 and 4 DRG cells exclusively expressed TTX-sensiti ve Na+ currents. Application of 5HT (1-10 mu M) increased TTX-insensit ive Na+ currents in type 2 DRG cells but did not affect Nai currents i n type 1, 3, or 4 DRG cells. The 5HT receptor involved resembled the 5 HT(4) subtype. It was activated by 5-methoxy-N,N-dimethyltryptamine (1 0 mu M) but not by 5-carboxyamidotryptamine (1 mu M), (+)-8-hydroxydip ropylaminotetralin (10 mu M), or 2-methyl-5HT (10 mu M), and was block ed by ICS 205-930 with an EC50 of similar to 2 mu M but not by ketanse rin (1 mu M). PGE(2) (4 or 10 mu M) also increased Na+ currents in var ying portions of cells in all four groups. The effect of 5HT and PGE(2 ) on Na+ currents was delayed for 20-30 sec after exposure to 5HT, sug gesting the involvement of a cytosolic diffusible component in the sig naling pathway. The agonist-mediated increase in Na+ current, however, was not mimicked by 8-chlorophenylthio-cAMP (200 mu M), suggesting th e possibility that cAMP was not involved. The data suggest that the 5H T- and PGE(2)-mediated increase in Na+ current may be involved in hype resthesia in different but overlapping subpopulations of nociceptors.