Antinociceptive activity of NK1 receptor antagonists: non‐specific effects of racemic RP67580

Abstract

Release of substance P in the dorsal horn is considered a primary event in the perception of pain. The profile of racemic RP67580, a non‐peptide antagonist at the NK1 (substance P) receptor, was examined in a range of antinociception tests on rodents. At doses up to 30 mg kg−1, s.c. racemic RP67580 exhibited antinociceptive activity in writhing and formalin paw tests in mice and gerbils. Acetic acid induced writhing and the licking response to formalin were reduced to 40–50% of the level observed in vehicle‐treated animals (P < 0.05). However, this agent was not active in mouse tail flick, rat paw pressure or rat and guinea‐pig formalin paw tests. Like racemic RP67580, the calcium channel blockers nifedipine (30 mg kg−1, i.p.) and verapamil (10 or 20 mg kg−1, s.c.) inhibited the response to formalin by approximately 60% in gerbils (P < 0.05 compared with vehicle‐treated animals). Evidence for calcium channel antagonist activity of RP67580 was obtained in vitro. Racemic RP67580 inhibited calcium entry into depolarized strips of guinea‐pig ileum longitudinal muscle myenteric plexus (apparent KB = 587 ± 115 nm), inhibited [3H]‐diltiazem binding to rabbit skeletal membranes (IC50 = 298 nm) and depressed high threshold calcium currents in neurones cultured from rat cortex (10% inhibition at 10 μm). These findings indicate that the acute antinociceptive effects of RP67580 may not be attributable to a specific interaction with NK1 receptors and may be mediated via calcium channel blockade. 1993 British Pharmacological Society