Role of peripheral 5-HT4, 5-HT6, and 5-HT7 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.