Formalin-induced nocicept1ve behavior and edema: Involvement of multiple peripheral 5-hydroxytryptamine receptor subtypes

The role of 5-hydroxytryptamine and its receptor subtypes in the development of acute inflammation was investigated using the rat paw formalin test as a model for pain (measured by flinching behavior) and edema formation (measured by plethysmometry). The role of endogenously released 5- hydroxytryptamine was assessed using 5-hydroxytryptamine receptor subtype- selective antagonists co-injected with 2.5% formalin, while the receptor subtypes involved in the inflammatory process were further defined by co- injection of 5-hydroxytryptamine or 5-hydroxytryptamine receptor subtype- selective agonists with 0.5% formalin in anticipation of an augmented response. When co-administered with 2.5% formalin, propranolol, tropisetron or GR113808A, but not ketanserin, effectively blocked nociceptive behavior. In the presence of 0.5% formalin, 5-carboxamidotryptamine, l-(m-chlorophenyl) biguanide or 5-methoxytryptamine, but not (±)-l-4-(4-iodo-2,5- dimethoxyphenyl)-2-aminopropane, augmented the flinching response. These data suggest involvement of 5-hydroxytryptamine₁, 5-hydroxytryptamine₃ and 5- hydroxytryptamine₄ receptors in peripheral nociception. There may be some dissociation of nociception and edema formation, since no single 5- hydroxytryptamine receptor antagonist inhibited edema formation with 2.5% formalin; however, with 0.5% formalin, edema formation was enhanced by co- administration of 5-hydroxytryptamine, 5-carboxamidotryptamine, (±)-1-4-(4- iodo-2,5-dimethoxyphenyl)-2-aminopropane or 5-methoxytryptamine, but not l- (m-chlorophenyl) biguanide. These data suggest involvement of 5- hydroxytryptamine₁, 5-hydroxytryptamine₂ and possibly 5-hydroxytryptamine₄ receptors in edema formation. These results confirm the involvement of 5- hydroxytryptamine₁ and 5-hydroxytryptamine₃ receptor subtypes in peripheral nociception associated with acute inflammation and further suggest an involvement of the more recently characterized 5-hydroxytryptamine₄ receptor in this process. There appears to be a dissociation in 5-hydroxytryptamine receptors involved in peripheral nociception and edema formation.