Evaluation of PD 154075, a Tachykinin NK1 Receptor Antagonist, in a Rat Model of Postoperative Pain

PD 154075 ([(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3) Ph) is a selective tachykinin NK1 receptor antagonist. Its effect on development and maintenance of thermal and mechanical hypersensitivity was examined in a rat model of surgical pain. When administered 30 min before surgery, PD 154075 dose-dependently (3-100 mg/kg, s.c.) prevented the development of thermal and mechanical hypersensitivity with respective minimum effective doses of 10 and 30 mg/kg. These antihypersensitivity effects lasted for 72 h. In contrast, the administration of PD 154075 (30 mg/kg, s.c.) after surgery had little or no effect on these nociceptive responses. PD 154075 antagonised thermal hypersensitivity induced by intrathecal administration of substance P, over the same dose range that blocked surgical hypersensitivity. However, it only partially blocked the thermal hypersensitivity induced by the selective NK2 receptor agonist [betaAla8]neurokinin A-(4-10). Morphine dose-dependently (1-6 mg/kg, s.c.) lengthened isoflurane and pentobarbitone-induced sleeping time in the rat. In contrast, PD 154075 (3-100 mg/kg, s.c.) did not interact with these anaesthetics. It is suggested that tachykinin NK1 receptor antagonists, such as PD 154075, may possess therapeutic potential as pre-emptive antihypersensitive agents.