title: Antinociceptive activity of NK1 receptor antagonists: non-specific effects of racemic RP67580.
abstract: 1. 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. 2. 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. 3. 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). 4. 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 microM). 5. 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.
authors.affiliation: Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex.
authors.forename: N M
authors.initials: NM
authors.lastname: Rupniak
authors.forename: S
authors.initials: S
authors.lastname: Boyce
authors.forename: A R
authors.initials: AR
authors.lastname: Williams
authors.forename: G
authors.initials: G
authors.lastname: Cook
authors.forename: J
authors.initials: J
authors.lastname: Longmore
authors.forename: G R
authors.initials: GR
authors.lastname: Seabrook
authors.forename: M
authors.initials: M
authors.lastname: Caeser
authors.forename: S D
authors.initials: SD
authors.lastname: Iversen
authors.forename: R G
authors.initials: RG
authors.lastname: Hill
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects; D004110:Diltiazem / Q000378:metabolism; D005849:Gerbillinae; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D054833:Isoindoles; D008297:Male; D051379:Mice; D064729:Neurokinin-1 Receptor Antagonists; D009543:Nifedipine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
chemical_list: D000700:Analgesics; D015220:Calcium Channels; D007211:Indoles; D054833:Isoindoles; D064729:Neurokinin-1 Receptor Antagonists; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; D004110:Diltiazem; D009543:Nifedipine