Serotonin receptor 5-HT_2B mediates serotonin-induced mechanical hyperalgesia

Serotonin [5-hydroxytryptamine (5-HT)] released from mast cells or platelets in peripheral tissues is one of the important inflammatory mediators in pain and hyperalgesia. The involvement of 5-HT in pain is complex because it could inhibit or facilitate nociceptive transmission, reflecting the presence of multiple 5-HT subtype receptors on peripheral and central nociceptors. The present study aimed to investigate the involvement of 5-HT_2B in 5-HT-induced pain and whether the subtype exists in dorsal root ganglion (DRG) neurons. Injecting the 5-HT or 5-HT₂ agonist in hindpaws of mice induced significant hyperalgesia to mechanical stimuli, which was inhibited by the 5-HT_2B/2C antagonist but not by 5-HT_1A, 5-HT _2A , or 5-HT_3A antagonists. Therefore, 5-HT_2B or 5-HT_2C may be involved in 5-HT-induced mechanical hyperalgesia. The 5-HT_2B/2C antagonist also blocked 5-HT-induced transient [Ca ²⁺] signaling in DRG neurons. All subtypes of 5-HT receptors except 5-HT_2C and 5-HT₆ are present in DRGs. In situ hybridization also demonstrated 5-HT_2B mainly expressed in small-to medium-diameter DRG neurons that respond to pain. Likely, 5-HT_2B mediates 5-HT-induced mechanical hyperalgesia in mice.