Control of sensory neuron excitability by serotonin involves 5HT2C receptors and Ca2+-activated chloride channels

- 5HT sensitizes TRPV1 channels in DRG neurons via 5HT2A, 5HT2B, as well as 5HT2C receptors.
- 5HT triggers inward currents through Ca2+-activated Cl- channels of DRG neurons via 5HT2C, but not 5HT2A or 2B receptors.
- 5HT causes an increase in action potential firing in DRG neurons that involves TRPV1 and Ca2+-activated Cl− channels.
- The increase in action potential firing in DRG neurons caused by 5HT involves 5HT2C, but not 5HT2A or 2B receptors.
- 5HT2C rather than 5HT2A or 2B receptors mediate the excitation of DRG neurons by 5HT.

Serotonin (5HT) is a constituent of the so-called “inflammatory soup” that sensitizes nociceptors during inflammation. Nevertheless, receptors and signaling mechanisms that mediate an excitation of dorsal root ganglion (DRG) neurons by 5HT remained controversial. Therefore, capsaicin-sensitive nociceptive neurons dissociated from rat DRGs were used to investigate effects of 5HT on membrane excitability and currents through ligand- as well as voltage-gated ion channels. In 58% of the neurons tested, 5HT increased action potential firing, an effect that was abolished by the 5HT2 receptor antagonist ritanserin, but not by the 5HT3 antagonist tropisetron. Unlike other algogenic mediators, such as PGE2 and bradykinin, 5HT did not affect currents through TTX-resistant Na+ channels or Kv7 K+ channels. In all neurons investigated, 5HT potentiated capsaicin-evoked currents through TRPV1 channels, an effect that was attenuated by antagonists at 5HT2A (4 F 4 PP), 5HT2B (SB 204741), as well as 5HT2C (RS 102221) receptors. 5HT triggered slowly arising inward Cl− currents in 53% of the neurons. This effect was antagonized by the 5HT2C receptor blocker only, and the current was prevented by an inhibitor of Ca2+-activated chloride channels (CaCC). The 5HT-induced increase in action potential firing was also abolished by this CaCC blocker and by the TRPV1 inhibitor capsazepine. Amongst the subtype selective 5HT2 antagonists, only RS 102221 (5HT2C-selectively) counteracted the rise in action potential firing elicited by 5HT. These results show that 5HT excites DRG neurons mainly via 5HT2C receptors which concomitantly mediate a sensitization of TRPV1 channels and an opening of CaCCs.