Evidence for the participation of peripheral 5-HT₂A, 5-HT₂B, and 5-HT₂C receptors in formalin-induced secondary mechanical allodynia and hyperalgesia.
The role of 5-HT₂A₂B₂C receptors in formalin-induced secondary allodynia and hyperalgesia in rats was assessed. Formalin produced acute nociceptive behaviors (flinching and lickinglifting) followed by long-term secondary mechanical allodynia and hyperalgesia. Pre-treatment for five consecutive days with compound 4880 (1, 3, 10, 10, and 10 μgpaw) prevented formalin-induced secondary allodynia and hyperalgesia. Ipsilateral, but not contralateral, peripheral pre-treatment (nmolpaw) with the 5-HT₂ receptor agonist DOI (3-30), 5-HT (10-100) or fluoxetine (0.3-3) significantly increased 0.5% formalin-induced secondary allodynia and hyperalgesia in both paws. The pronociceptive effect of DOI (10 nmolpaw), 5-HT (100 nmolpaw) and fluoxetine (1 nmolpaw) was blocked by selective 5-HT₂A (ketanserin), 5-HT₂B (RS-127445), and 5-HT₂C (RS-102221) receptor antagonists. Furthermore, ipsilateral pre-treatment (nmolpaw) with ketanserin (1, 10, and 100), RS-127445 (0.01, 0.1 and 1) or RS-102221 (1, 10 and 100) prevented while post-treatment reversed 1% formalin-induced secondary allodynia and hyperalgesia in both paws. In marked contrast, contralateral injection of the greatest tested dose of 5-HT₂A₂B₂C receptor antagonists did not modify long-lasting secondary allodynia and hyperalgesia. These results suggest that 5-HT released from mast cells after formalin injection sensitizes primary afferent neurons via 5-HT₂A₂B₂C receptors leading to the development and maintenance of secondary allodynia and hyperalgesia.