Role of peripheral 5-HT(4), 5-HT(6), and 5-HT(7) receptors in development and maintenance of secondary mechanical allodynia and hyperalgesia

The role of 5-hydroxytryptamine (5-HT)₄, 5-HT₆, and 5-HT₇ receptors in formalin-induced secondary allodynia and hyperalgesia in rats was assessed. Formalin produced acute nociceptive behaviors (flinching and licking/lifting) followed by long-term secondary mechanical allodynia and hyperalgesia. Pretreatment (−10 min) with cromoglycate (195-1950 nmol/paw) partially inhibited acute nociceptive behaviors and completely prevented secondary allodynia and hyperalgesia on day 6 after injection. Ipsilateral peripheral pretreatment with the selective 5-HT₄ (ML-10302, 1-100 nmol/paw), 5-HT₆ (EMD-386088, 0.001-0.01 nmol/paw), and 5-HT₇ (LP-12, 0.01-100 nmol/paw) receptor agonists significantly increased secondary allodynia and hyperalgesia in both paws. In contrast, ipsilateral peripheral pretreatment with the selective 5-HT₄ (GR-125487, 1-100 nmol/paw), 5-HT₆ (SB-258585, 0.00001-0.001 nmol/paw), and 5-HT₇ (SB-269970, 0.1-10 nmol/paw) receptor antagonists significantly prevented formalin-induced secondary allodynia and hyperalgesia in both paws. The pronociceptive effect of ML-10302 (100 nmol/paw), EMD-386088 (0.01 nmol/paw), and LP-12 (100 nmol/paw) were completely prevented by GR-125487 (5-HT₄ antagonist, 1 nmol/paw), SB-258585 (5-HT₆ antagonist, 0.00001 nmol/paw), and SB-269970 (5-HT₇, antagonist, 0.01 nmol/paw), respectively. Ipsilateral peripheral posttreatment with cromoglycate or GR-125487 (1-100 nmol/paw), SB-258585 (0.001-0.1 nmol/paw), and SB-269970 (0.1-10 nmol/paw) reversed formalin-induced secondary allodynia and hyperalgesia in both paws. Results suggest that a barrage of afferent input induced by 5-HT at peripheral 5-HT₄, 5-HT₆, and 5-HT₇ receptors participate in the development and maintenance of formalin-induced long-term secondary allodynia and hyperalgesia in the rat.