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.