Effects of FK224, a Novel Cyclopeptide NK1 and NK2 Antagonist, and CP-96,345, a Nonpeptide NK1 Antagonist, on Development and Maintenance of Thermal Hyperesthesia Evoked by Carrageenan Injection in the Rat Paw

Abstract

The role of tachykinins, such as substance P and neurokinin A, in the development or maintenance of thermal hyperesthesia during inflammation is unclear. In the current study, the authors examined the role of NK1 and NK2 receptors on the thermal hyperesthesia evoked by injection of carrageenan into the rat paw using FK224, a cyclopeptide NK1 and NK2 antagonist, and CP-96,345, a nonpeptide NK1 antagonist. In rats injected with 2 mg carrageenan, the paw withdrawal latency (PWL) for the injected paw was typically 5-6 s less than that for the untreated paw, at 2 h after the carrageenan injection. In the pretreatment study, drugs were administered intravenously or intrathecally 10 min before the carrageenan injection. In the posttreatment study, drugs were administered intravenously or intrathecally 2 h after the carrageenan injection. In the pretreatment study, both intravenous CP-96,345 and intravenous FK224 blocked the development of thermal hyperesthesia and reduced paw edema in a dose-dependent manner 2 h after the carrageenan injection. The effect of CP-96,345 on thermal hyperesthesia was stereospecific, but that on paw edema was not. Posttreatment with intravenous CP-96,345 and intravenous FK224 failed to reduce the level of thermal hyperesthesia or paw edema, and intrathecal injections, either pre- or posttreatment, had no effect on thermal hyperesthesia or paw edema. These data indicate that: 1) spinal NK1 and NK2 receptors do not play an important role in development and maintenance of thermal hyperesthesia evoked by paw carrageenan, and 2) the peripheral NK1 receptor may play an important role in the development of thermal hyperesthesia, but not of paw edema.