EVALUATION OF PD154075, A TACHYKININ NK1 RECEPTOR ANTAGONIST, IN A RAT MODEL OF POSTOPERATIVE PAIN

PD 154075 nzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3)Ph) is a sele ctive tachykinin NK1 receptor antagonist. Its effect on development an d maintenance of thermal and mechanical hypersensitivity was examined in a rat model of surgical pain. When administered 30 min before surge ry. PB 154075 dose-dependently (3-100 mg/kg, s.c.) prevented the devel opment of thermal and mechanical hypersensitivity with respective mini mum effective doses of 10 and 30 mg/kg. These antihypersensitivity eff ects 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 nocicepti ve responses. PD 154075 antagonised thermal hypersensitivity induced b y intrathecal administration of substance P. over the same dose range that blocked surgical hypersensitivity. However, it only partially blo cked the thermal hypersensitivity induced by the selective NK2 recepto r agonist [beta Ala(8)]neurokinin A-(4-10). Morphine dose-dependently (1-6 mg/kg, s.c.) lengthened isoflurane and pentobarbitone-induced sle eping 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 p otential as pre-emptive antihypersensitive agents. (C) 1998 Elsevier S cience B.V.